Bicyclic compounds

ABSTRACT

Compounds of the general formula (I): 
                 
 
or a salt thereof, wherein R 1  is hydrogen, hydroxyl or halogen; R 2  is NHSO 2 CH 3 , SO 2 NHCH 3  or the like; R 5  and R 6  each independently is hydrogen, C 1-6  alkyl, optionally substituted phenyl or optionally substituted benzyl; X is NH, sulfur, oxygen or methylene; Y is oxygen, NR 7 , sulfur, methylene or a bond; and * represents an asymmetric carbon atom. The compounds are useful as a medicine for treating or preventing diabetes, obesity, hyperlipidemia, digestive diseases, depression or urinary disturbances.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of co-pending application Ser. No.10/258,817, filed on Oct. 28, 2002. application Ser. No. 10/258,817 isthe national phase of PCT International Application No. PCT/JP01/03575filed on Apr. 25, 2001 under 35 U.S.C. § 371. The entire contents ofeach of the above-identified applications are hereby incorporated byreference

FIELD OF THE INVENTION

This invention relates to novel compounds which are useful as a medicinefor treating and preventing diabetes, obesity, hyperlipidemia, digestivediseases, depression and urinary disturbances.

BACKGROUND OF THE INVENTION

Beta-adrenoreceptors are classified into three classes,β1-adrenoreceptor, β2-adrenoreceptor and β3-adrenoreceptor, and it isrecognized that stimulation of β1 induces an increase in the heart rateand stimulation of β2 induces a relaxation of the smooth muscle tissue,thereby resulting in lowering the blood pressure. It is also recognizedthat stimulation of β3 facilitates the lipolysis in adipocytes, therebyresulting in increasing the thermogenesis. Therefore, compounds havingβ3-agonist activity were shown to be useful as a medicine for treatingand preventing diabetes, obesity and hyperlipidemia (Nature, vol. 309,pp. 163-165 (1984); Int. J. Obes. Relat. Metab. Disord., vol. 20, pp.191-199 (1996); Drug Development Research, vol. 32, pp. 69-76 (1994); J.Clin. Invest., vol. 101, pp. 2387-2393 (1998)). Recently, it was shownthat β3-adrenoreceptor is expressed in the detrusor and a β3-agonistinduces a relaxation of the detrusor (J. Urinol., vol. 161, pp. 680-685(1999); J. Pharmacol. Exp. Ther., vol. 288, pp. 1367-1373 (1999)).

Some compounds showing a β3-agonist activity have been known. Compoundshaving high selectivity or having low β1- and β2-stimulating activitiesare particularly required when their usefulness as a medicine is takeninto consideration. This is because compounds having both β1- andβ2-stimulating activities induce side effects such as increase in theheart rate and lowering of the blood pressure, as set forth above.

So far, the following compounds have been exemplified as compoundsrelating to β3:the compound (BRL 37344) having the following structural formuladescribed in EP 023385 and the literature (Drugs of the future, vol. 16,p. 797 (1991)):

the compound (CL 316,243) having the following structural formuladescribed in EP 0455006 and the literature (J. Med. Chem., vol. 35, p.3081 (1992)):

andthe compound having the following structural formula described in WO94/29290:

Further, EP 0659737 discloses a variety of compounds and specificallydescribes as an example in Example 1 in the text of specification thecompound having the following structural formula:

However, the chemical structures of the above compounds are clearlydistinct from those of the claimed compounds of the present invention.

In addition, the compound described in EP 171702 and having thefollowing structural formula:

has been known as having heart rate-increasing activity, myocardialcontraction enhancement and antiobestic activity. However, this compoundacts on the heart and is different from the compounds of the presentinvention in the chemical structure and in that the former strongly actson the heart.

Further, the compound described in JP-A-55-53262 and JP-A-58-41860 andhaving the following structural formula:

is known as having α,β-blocking activity, namely, the effect of loweringblood pressure; and the compound described in DE 2651572 and having thefollowing structural formula:

is known as having vasodilator action. However, these compounds aredifferent from the compounds of the present invention in their chemicalstructures and intended uses.

The present inventors formerly invented compounds having excellentβ3-agonist activity and disclosed compounds represented by, for example,the following structural formula in WO 97/25311.

The above compounds, however, are different from the compounds of thepresent invention in their chemical structures.

SUMMARY OF THE INVENTION

Compounds useful as a medicine for treating or preventing diabetes,obesity, hyperlipidemia, digestive diseases, depression or urinarydisturbances are represented by the general formula (I):

or a salt thereof, wherein R¹ is hydrogen, hydroxyl or halogen; R² isNHSO₂CH₃, SO₂NHCH₃ or the like; R⁵and R⁶ each independently is hydrogen,C₁₋₆ alkyl, optionally substituted phenyl or optionally substitutedbenzyl; X is NH, sulfur, oxygen or methylene; Y is oxygen, NR⁷, sulfur,methylene or a bond; and * represents an asymmetric carbon atom.

DISCRIPTION OF PREFERRED EMBODIMENTS

There has been a need for a novel and useful β3-selective agonist whichcan be used for treating and preventing diabetes, obesity,hyperlipidemia, urinary disturbances and the like.

In order to solve the above problems, the present inventors have foundthat a novel compound of the general formula (I) set forth below hasselective β3-agonist activity.

That is, the present invention relates to a compound of the generalformula (I):

or a salt thereof,wherein

R¹ represents a hydrogen atom, a hydroxyl group or a halogen atom;

R² represents NHSO₂R³ or SO₂NR⁴R^(4′);

R³ represents an alkyl group containing from 1 to 6 carbon atoms, abenzyl group, a phenyl group or NR⁴R^(4′);

R⁴ and R^(4′) may be the same or different and each independentlyrepresents a hydrogen atom or an alkyl group containing from 1 to 6carbon atoms;

R⁵ and R⁶ may be the same or different and each independently representsa hydrogen atom, an alkyl group containing from 1 to 6 carbon atoms, anoptionally substituted phenyl group or an optionally substituted benzylgroup;

X represents NH, a sulfur atom, an oxygen atom or a methylene group;

Y represents an oxygen atom, NR⁷, a sulfur atom, a methylene group or abond;

R⁷ represents a hydrogen atom, an alkyl group containing from 1 to 6carbon atoms, or an acyl group containing from 1 to 6 carbon atoms; and

* represents an asymmetric carbon atom.

Unless otherwise specified, “a halogen atom” used herein means afluorine, chlorine, bromine or iodine atom. In addition, “an alkyl groupcontaining from 1 to 6 carbon atoms” means a straight or branchedsaturated hydrocarbon group containing from 1 to 6 carbon atoms andspecifically means methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, tert-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl group orthe like. Further, “an acyl group containing from 1 to 6 carbon atoms”means a carbonyl group attached to a hydrogen atom or a straight orbranched saturated hydrocarbon group containing from 1 to 5 carbon atomsand specifically means formyl, acetyl, propionyl, butanoyl, pentanoyl,hexanoyl group or the like.

R¹ represents a hydrogen atom, a hydroxyl group or a halogen atom.Preferred examples thereof include a hydrogen atom, a hydroxyl group, afluorine atom, a chlorine atom and a bromine atom. Although the positionon the benzene ring at which R¹ is attached is not limited, the positionis preferably ortho- or para-position with respect to the aminoethanolside-chain, with para-position (2-position) being particularlypreferred.

R² represents NHSO₂R³ or SO₂NR⁴R^(4′) wherein R³ represents an alkylgroup containing from 1 to 6 carbon atoms, a benzyl group, a phenylgroup or NR⁴R^(4′) and wherein R⁴ and R^(4′) may be the same ordifferent and each independently represents a hydrogen atom or an alkylgroup containing from 1 to 6 carbon atoms. Among the above, particularlypreferred examples of R² include NHSO₂CH₃, SO₂NHCH₃, NHSO₂N(CH₃)₂ andthe like.

Within the combinations of R¹ and R², the combination in which R¹ is ahydrogen, fluorine, chlorine or bromine atom at para-position(2-position) and R² is NHSO₂R³ is preferred. The combination in which R¹is a hydroxyl group at para-position (2-position) and R² is SO₂NR⁴R^(4′)is also preferred.

R⁵ and R⁶ may be the same or different and represent a hydrogen atom, analkyl group containing from 1 to 6 carbon atoms, an optionallysubstituted phenyl group or an optionally substituted benzyl group.Particularly preferably, R⁵ is a methyl group and R⁶ is an optionallysubstituted phenyl group.

The abovementioned substituent which may exist on the benzene ring is ahydroxyl group, a halogen atom, a trifluoromethyl group, a lower alkylgroup, a lower alkoxy group, a lower acyl group, NRR′, a nitro groupand/or a cyano group. R and R′ may be the same or different andrepresent a hydrogen atom, a lower alkyl group, a lower acyl group, abenzyl group or SO₂R″. R″ represents a lower alkyl group or a benzylgroup. The term “lower” means a straight or branched substituentcontaining from 1 to 6 carbon atoms. The number of the substituents onthe phenyl group is from 1 to 5, preferably from 1 to 2.

X represents NH, an oxygen atom, a sulfur atom or a methylene group,with NH being more preferred.

Y represents an oxygen atom, NR⁷, a sulfur atom, a methylene group or abond. In addition, R⁷ represents a hydrogen atom, an alkyl groupcontaining from 1 to 6 carbon atoms or an acyl group containing from 1to 6 carbon atoms. Y is preferably an oxygen atom, NR⁷ or a sulfur atom,more preferably an oxygen atom or NH.

In the general formula (I) set forth above, * is an asymmetric carbonatom, and the compound of the general formula (I) can be in the form ofany of two enantiomers, R-enantiomer and S-enantiomer. Not onlyoptically pure isomers, but also mixtures of the two isomers with anymixing ratio are encompassed in the present invention. From theviewpoint of the expression of pharmacological activity, a preferredconfiguration of the asymmetric carbon * is the configuration R.

In addition, illustrative examples of specific compounds of the generalformula (I) of the present invention include the following racemiccompounds and optical isomers thereof.

-   N-[3-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;-   N-methyl-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide;-   N-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;-   N-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide;-   N-[3-[2-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;-   N-methyl-[5-[2-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy)benzenesulfonamide;-   N-[5-[2-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;-   N-[5-[2-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide;-   N-[3-[2-[2-(2-methyl-3-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;-   N-methyl-[5-[2-[2-(2-methyl-3-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide;-   N-[5-[2-[2-(2-methyl-3-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;-   N-[3-[2-[2-(2,3-dimethylbenzofuran-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;-   N-methyl-[5-[2-[2-(2,3-dimethylbenzofuran-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide;-   N-[5-(2-[2-(2,3-dimethylbenzofuran-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;-   N-[3-[2-[2-(2,3-dimethylbenzothiophen-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;-   N-methyl-[5-[2-[2-(2,3-dimethylbenzothiophen-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide;    and-   N-[5-[2-[2-(2,3-dimethylbenzothiophen-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide.

Processes for the preparation of compounds represented by the generalformula (I) are illustrated in the following.

Preparation Process A

Compounds of the general formula (I) may be prepared according to theprocesses described in WO 97/25311 and WO 00/58287. That is, anobjective compound of the general formula (I) may be prepared by, as thefirst step, reacting a compound represented by the general formula (II):

wherein R⁵, R⁶, X and Y are as defined above, and W represents ahydrogen atom or an amino-protecting group, with a compound representedby the general formula (III):

wherein R^(1′) represents a hydrogen atom, OR⁹ or a halogen atom, R⁹represents a hydroxyl-protecting group, L² represents a leaving group,R^(2′) represents NW² SO₂R³ or SO₂NR⁴R^(4′), W² represents a hydrogenatom or an amino-protecting group, and R³, R⁴ and R^(4′) are as definedabove, to give an amino ketone (—CO—CH₂—NW—) compound; as the secondstep, reducing the thus obtained amino ketone compound to give an aminoalcohol (—CHOH—CH₂—NW—) compound; and, as the final step, optionallyremoving the hydroxyl-protecting group R⁹ on the benzene ring and, whenW and W² are not hydrogen atoms but amino-protecting groups, removingthem. Examples of L² include a chlorine atom, a bromine atom, an iodineatom and the like. When W and W² are an amino-protecting group, theamino-protecting group is not limited as long as it is a protectinggroup used in a common organic synthesis. Preferred examples of theamino-protecting group include a benzyl group, a substituted benzylgroup and the like. When R^(1′) is OR⁹, the hydroxyl-protecting group R⁹is not limited as long as it is a protecting group used in a commonorganic synthesis. Preferred examples of the hydroxyl-protecting groupinclude a benzyl group, a substituted benzyl group and the like. Theamount of the compound represented by the general formula (II) to beused in the first step is from 1 to 5 mol for 1 mol of the compoundrepresented by the general formula (III). A base may be added toneutralize an acid generated by the reaction. Examples of the base to beused include organic bases such as triethylamine, diisopropylethylamineand pyridine, inorganic bases such as potassium carbonate, sodiumhydrogencarbonate and sodium hydroxide and the like. Further, compoundsof the general formula (II) may be used also in the form of their salts,provided that the abovementioned base is added. Examples of the solventto be used in the reaction include lower alcohols such as methanol,ethanol and isopropyl alcohol, chlorinated hydrocarbons such asmethylene chloride, chloroform and 1,2-dichloroethane, tetrahydrofuran,dimethylformamide, dimethylsulfoxide and the like, withdimethylformamide being preferred. Although reaction temperature andreaction time are not limited, the reaction is carried out at atemperature of from −30° C. to the boiling point of the selectedsolvent, preferably a temperature of from 0° C. to 30° C., for 10minutes to 24 hours. The amino ketone generated in the first step may beused in the reductive reaction of the second step without separationfrom the reaction mixture. However, the amino ketone may be optionallyextracted and purified before the reductive reaction. Examples of thereducing agent to be used include sodium borohydride, sodiumcyanoborohydride, borane and the like. Examples of the solvent to beused in the reaction include lower alcohols such as methanol, ethanoland isopropyl alcohol, tetrahydrofuran, dimethylformamide,dimethylsulfoxide, and the like, with ethanol and dimethylformamidebeing preferred. Although reaction temperature and reaction time are notlimited, the reaction is carried out at a temperature of from −30° C. tothe boiling point of the selected solvent, preferably a temperature offrom 0° C. to 30° C., for 10 minutes to 24 hours. When the removal ofthe amino-protecting group and/or hydroxyl-protecting group is needed asthe final step, they may be removed under reaction conditions usuallyused for removing the protecting groups to be used. When a benzyl orsubstituted benzyl group is used as the protecting group, it may beremoved, for example, by a hydrogenation reaction usingpalladium/activated carbon as a catalyst. Compounds represented by thegeneral formula (I), which contain an asymmetric carbon represented by*, are obtained as a racemic mixture by the process set forth above. Theracemic mixture can be optically resolved into two optically activesubstances by converting the racemic mixture to acid addition salts withan optically active acid such as camphorsulfonic acid or mandelic acidfollowed by a fractional crystallization treatment. The racemic mixturemay be also optically resolved using a commercially available opticallyactive column.

Further, optically active substances may be also obtained by carryingout an asymmetric reduction treatment with a hydrogen donating compoundin the presence of an asymmetric reduction catalyst in the second stepaccording to the process described in WO 00/58287.

Preparation Process B

In addition, compounds of the general formula (I) may be also preparedby another process set forth below according to the processes describedin WO 97/25311 and WO 01/04092. That is, an objective compound of thegeneral formula (I) may be prepared by, as the first step, reacting acompound represented by the formula (II) with a compound represented bythe formula (IV):

wherein L² represents a leaving group, R⁸ represents ahydroxyl-protecting group, and R^(1′), R^(2′) and * are as definedabove, to give an amino ether (—CHOR⁸—CH₂—NHW—) compound; and, as thesecond step, removing the hydroxyl-protecting group R⁸, optionallyremoving the hydroxyl-protecting group R⁹, and when W and W² are nothydrogen atoms but amino-protecting groups, removing them. Examples ofL² include a chlorine atom, a bromine atom, an iodine atom and the like,with iodine atom being preferred. W and W² are as set forth above inPreparation Process A. The hydroxyl-protecting group R⁹ when R^(1′) isOR⁹ is also as set forth above in Preparation Process A. Anotherhydroxyl-protecting group R⁸ is not limited as long as it is aprotecting group used in a common organic synthesis. Preferred examplesof the hydroxyl-protecting group include a triethylsilyl group. Theamount of the compound represented by the general formula (II) to beused is from 1 to 1.5 mol for 1 mol of the compound represented by thegeneral formula (IV). A base may be added to neutralize an acidgenerated by the reaction. Examples of the base to be used includetriethylamine, diisopropylethylamine and the like. Further, compounds ofthe general formula (II) may be used also in the form of their salts,provided that the abovementioned base is added. Examples of the solventto be used in the reaction include dimethylformamide, dimethylacetamide,dimethylsulfoxide and the like, with dimethylformamide being preferred.Although reaction temperature and reaction time are not limited, thereaction is carried out at a temperature of from 0° C. to 90° C.,preferably a temperature of 60° C., for 10 minutes to 24 hours. Thehydroxyl-protecting group R⁸ and optionally the other protecting groupsmay be removed under reaction conditions usually used for removing theprotecting groups to be used. A triethylsilyl group as R⁸ may be removedusing, for example, tetrabutylammonium fluoride. Optically activesubstances may be prepared as set forth above in Preparation Process Aby formation of acid addition salts with an optically active acidfollowed by a fractional crystallization treatment, or opticalresolution using a commercially available optically active column or thelike.

Further, an optically active compound represented by the generalformula(I) may be also prepared using an optically active compoundrepresented by the general formula (IV) prepared according to theprocesses described in, for example, WO 97/25311 and WO 01/04092.

Compounds represented by the general formula (III) are known compoundsand may be prepared by the process described in, for example, WO97/25311 or the literature (J. Med. Chem., vol. 10, p. 462 (1966)).Further, compounds represented by the general formula (IV) are knowncompounds and may be prepared by the process described in, for example,WO 97/25311.

Compounds represented by the general formula (II) are characteristic asimportant intermediates for synthesizing compounds represented by thegeneral formula (I) and are novel compounds except that both of R⁵ andR⁶ represent a hydrogen atom. Processes for the preparation of compoundsrepresented by the general formula (II) are illustrated in thefollowing.

Preparation Process C

Compounds represented by the general formula (II) wherein Y is an oxygenatom may be prepared by the process set forth below. That is, anobjective compound may be obtained by reacting a compound represented bythe general formula (V):

wherein Y represents an oxygen atom, and R⁵, R⁶ and X are as definedabove, with a compound represented by the general formula (VI):

wherein L¹ represents a leaving group, and W¹ represents anamino-protecting group, in the presence of a base; as the second step,removing the amino-protecting group W¹; and, as the final step,optionally re-protecting this amino group with another protecting groupW. Even if W is a hydrogen atom (i.e. the amino group is in the freeform), the compound may be used in the following reaction. Examples ofL¹ include a chlorine atom, a bromine atom, an iodine atom and the like.The amino-protecting group W¹ is not limited as long as it is aprotecting group used in a common organic synthesis. Preferred examplesinclude a benzyloxycarbonyl group, a substituted benzyloxycarbonylgroup, a tert-butoxycarbonyl group and the like. W may be selected asset forth above in Preparation Process A for compounds of the formula(I). The amount of the compound represented by the general formula (VI)to be used in the first step is from 1 to 5 mol for 1 mol of thecompound represented by the general formula (V). Examples of the base tobe used include potassium carbonate, sodium carbonate, potassiumhydroxide, sodium hydroxide, sodium hydride, sodium methoxide,triethylamine and the like. Examples of the solvent to be used in thereaction include tetrahydrofuran, dimethylformamide, dimethylacetamide,dimethylsulfoxide, acetonitrile and the like. Although reactiontemperature and reaction time are not limited, the reaction is carriedout at a temperature of from 0° C. to the boiling point of the selectedsolvent, preferably a temperature of from room temperature to 90° C.,for 10 minutes to 24 hours. In the second step, the amino-protectinggroup W¹ may be removed under reaction conditions usually used forremoving the protecting group to be used. When a benzyloxycarbonyl orsubstituted benzyloxycarbonyl group is used as the protecting group, itmay be removed, for example, by a hydrogenation reaction usingpalladium/activated carbon as a catalyst. When a tert-butoxycarbonylgroup is used as the protecting group, it may be removed using an acidsuch as trifluoroacetic acid or hydrochloric acid.Preparation Process D

Compounds represented by the general formula (II) wherein Y is a sulfuratom may be prepared by the process set forth below. That is, anobjective compound may be obtained by reacting a compound represented bythe general formula (V):

wherein Y represents a sulfur atom, and R⁵, R⁶ and X are as definedabove, with a hydrochloride or hydrobromide salt of a compoundrepresented by the general formula (VI):

wherein W¹ represents a hydrogen atom, and L¹ represents a chlorine atomor a bromine atom. The amount of the compound represented by the generalformula (VI) to be used is from 1 to 1.5 mol for 1 mol of the compoundrepresented by the general formula (V). The reaction is usually carriedout in the presence of a base. Examples of the base include organicbases such as triethylamine, diisopropylethylamine and pyridine,inorganic bases such as potassium carbonate, sodium hydrogencarbonate,sodium hydroxide and the like. Examples of the solvent to be used in thereaction include lower alcohols such as methanol, ethanol and isopropylalcohol, acetic acid, chlorinated hydrocarbons such as methylenechloride, chloroform and 1,2-dichloroethane, tetrahydrofuran,dimethylformamide, dimethylsulfoxide and the like, which may be usedalone or as a mixed solvent comprising plural solvents. Preferably, amixed solvent of tetrahydrofuran and methanol is used. Although reactiontemperature and reaction time are not limited, the reaction is carriedout at a temperature of from −30° C. to the boiling point of theselected solvent, preferably a temperature of from 0° C. to 30° C., for10 minutes to 24 hours.Preparation Process E

Compounds represented by the general formula (II) wherein Y is NR⁷ maybe prepared by the process set forth below. That is, an objectivecompound may be obtained by, as the first step, reacting a compoundrepresented by the general formula (V):

wherein Y represents NR⁷, and R⁵, R⁶, R⁷ and X are as defined above,with a compound represented by the general formula (VII):

wherein W¹ represents an amino-protecting group, in the presence of areducing agent; as the second step, removing the amino-protecting groupW¹; and, as the final step, optionally re-protecting this amino groupwith another protecting group W. Even if W is a hydrogen atom (i.e. theamino group is in the free form), the compound may be used in thefollowing reaction. The amino-protecting group W¹ is not limited as longas it is a protecting group used in a common organic synthesis.Preferred examples include a benzyloxycarbonyl group, a substitutedbenzyloxycarbonyl group, a tert-butoxycarbonyl group and the like. W maybe selected as set forth above in Preparation Process A for compounds ofthe formula (I). The amount of the compound represented by the generalformula (VII) to be used in the first step is from 1 to 1.5 mol for 1mol of the compound represented by the general formula (V). Examples ofthe reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, sodium borohydride, lithium cyanoborohydrideand the like. Examples of the solvent to be used in the reaction includelower alcohols such as methanol, ethanol and isopropyl alcohol, aceticacid, chlorinated hydrocarbons such as methylene chloride, chloroformand 1,2-dichloroethane, tetrahydrofuran and the like, withtetrahydrofuran being preferred. Although reaction temperature andreaction time are not limited, the reaction is carried out at atemperature of from −30° C. to the boiling point of the selectedsolvent, preferably a temperature of from 0° C. to 30° C., for 10minutes to 24 hours. In the second step, the amino-protecting group W¹may be removed under reaction conditions usually used for removing theprotecting group to be used. When a benzyloxycarbonyl or substitutedbenzyloxycarbonyl group is used as the protecting group, it may beremoved, for example, by a hydrogenation reaction usingpalladium/activated carbon as a catalyst. When a tert-butoxycarbonylgroup is used as the protecting group, it may be removed using an acidsuch as trifluoroacetic acid or hydrochloric acid.

Compounds represented by the general formula (II) wherein Y is amethylene group or a bond may be prepared by or according to the knownprocess described in the literature (Troxler et al., Helv. Chim. Acta.,vol. 51, p. 1616 (1968)). Further, compounds represented by the generalformula (II) wherein Y is a methylene group or a bond may be alsoprepared according to the known process for preparing indolederivatives, the known process for preparing benzofuran derivatives, theknown process for preparing benzothiophene derivatives or the knownprocess for preparing indene derivatives.

Compounds represented by the general formula (V):

wherein Y represents NR⁷, and R⁵, R⁶, R⁷ and X are as defined above maybe prepared by or according to the known processes set forth below.

That is, a compound of the formula (V) wherein X=NH, Y=O, R⁵=H and R⁶=Hmay be synthesized by the process described in the literature (Sheppardet al., J. Med. Chem., vol. 37, p. 2011 (1994)). Likewise, a compound ofthe formula (V) wherein X=NH, Y=O, R⁵=CH₃ and R⁶=H may be synthesized bythe process described in the literature (Ito et al., J. Am. Chem. Soc.,vol. 117, p. 1485 (1995)). A compound of the formula (V) wherein X=NH,Y=O, R⁵=CH₃ and R⁶=CH₃ may be synthesized by the process described inthe literature (Ockenden et al., J. Chem. Soc., p. 3175 (1957)). Acompound of the formula (V) wherein X=NH, Y=O, R⁵=H and R⁶=CH₃ and acompound of the formula (V) wherein X=O, R⁵=H and R⁶=CH₃ may besynthesized by the process described in the literature (Baxter et al.,Aust. J. Chem., vol. 27, p. 2605 (1974)). A compound of the formula (V)wherein X=NH, Y=O, R⁵=H and R⁶=phenyl may be synthesized by the processdescribed in DE-2612057. A compound of the formula (V) wherein X=NH,Y=O, R⁵=phenyl and R⁶=H may be synthesized by the process described inthe literature (Morton et al., J. Biol. Chem., vol. 179, p. 259 (1949)).A compound of the formula (V) wherein X=NH, Y=O, R⁵=phenyl and R⁶=phenylmay be synthesized by the process described in the literature (Teuber etal., Chem. Ber., vol. 91, p. 2089 (1958)). A compound of the formula (V)wherein X=O, Y=O, R⁵=H and R⁶=H may be synthesized by the processdescribed in the literature (Foster et al., J. Chem. Soc., p. 2254(1948)). A compound of the formula (V) wherein X=O, Y=O, R⁵=CH₃ and R⁶=Hmay be synthesized by the process described in the literature (Henningset al., Tetrahedron Lett., vol. 38, p. 6379 (1997)). A compound of theformula (V) wherein X=O, Y=O, R⁵=CH₃ and R⁶=CH₃ may be synthesized bythe process described in the literature (Bisagni et al., Bull. Soc.Chim. Fr., p. 925 (1962)). A compound of the formula (V) wherein X=O,Y=O, R⁵=H and R⁶=isopropyl may be synthesized by the process describedin the literature (Kawase et al., Bull. Chem. Soc. Japan, vol. 35, p.1624 (1962)). A compound of the formula (V) wherein X=O, Y=O, R⁵=H andR⁶=phenyl may be synthesized by the process described in the literature(Deschamps et al., Tetrahedron Lett., p. 1109 (1979)). A compound of theformula (V) wherein X=O, Y=O, R⁵=phenyl and R⁶=H, a compound of theformula (V) wherein X=O, Y=O, R⁵=phenyl and R⁶=CH₃, a compound of theformula (V) wherein X=S, Y=O, R⁵=CH₃ and R⁶=H, and a compound of theformula (V) wherein X=S, Y=O, R⁵=CH₃ and R⁶=CH₃ may be synthesized bythe process described in the literature (Royer et al., Bull. Soc. Chim.Fr., p. 942 (1961)). A compound of the formula (V) wherein X=O, Y=O,R⁵=phenyl and R⁶=phenyl may be synthesized by the process described inthe literature (Hishmat et al., Indian J. Chem., vol. 13, p. 479(1975)). A compound of the formula (V) wherein X=S, Y=O, R⁵=H and R⁶=Hmay be synthesized by the process described in the literature (Perold etal., Chem. Ber., vol. 92, p. 293 (1959)). A compound of the formula (V)wherein X=S, Y=O, R⁵=H and R⁶=phenyl may be synthesized by the processdescribed in the literature (Fries et al., Justus Liebigs Ann. Chem.,vol. 527, p. 83 (1937)). A compound of the formula (V) wherein X=S, Y=O,R⁵=phenyl and R⁶=phenyl may be synthesized by the process described inthe literature (Marcuzzi et al., Synthesis, p.451 (1976)). A compound ofthe formula (V) wherein X=CH₂, Y=O, R⁵=C₂H₅ and R⁶=phenyl may besynthesized by the process described in the literature (Anstead et al.,J. Org. Chem., vol. 54, p. 1485 (1989)). A compound of the formula (V)wherein X=CH₂, Y=O, R⁵=phenyl and R⁶=phenyl may be synthesized by theprocess described in the literature (Anstead et al., J. Med. Chem., vol.31, p. 1316 (1988)). A compound of the formula (V) wherein X=NH, Y=NH,R⁵=H and R⁶=H may be synthesized by the process described in theliterature (Yee et al., J. Med. Chem., vol. 33, p. 2437 (1990)). Acompound of the formula (V) wherein X=NH, Y=NH, R⁵=CH₃ and R⁶=CH₃ may besynthesized by the process described in the literature (Brown et al., J.Am. Chem. Soc., vol. 74, p. 3934 (1952)). A compound of the formula (V)wherein X=NH, Y=NH, R⁵=phenyl and R⁶=CH₃ may be synthesized by theprocess described in the literature (Borshe et al., Chem. Ber., vol. 42,p. 611 (1909)). A compound of the formula (V) wherein X=NH, Y=NH,R⁵=phenyl and R⁵=phenyl may be synthesized by the process described inthe literature (Kinsley et al., J. Chem. Soc., p. 1 (1958)). A compoundof the formula (V) wherein X=O, Y=NH, R⁵=H and R⁶=H may be synthesizedby the process described in the literature (Gansser et al., Helv. Chim.Acta., vol. 37, p. 437 (1954)). A compound of the formula (V) whereinX=O, Y=NH, R⁵=CH₃ and R⁶=CH₃ may be synthesized by the process describedin the literature (Kawase et al., Bull. Chem. Soc. Japan, vol. 44, p.749 (1971)). A compound of the formula (V) wherein X=O, Y=NH, R⁵=H andR⁶=phenyl may be synthesized by the process described in the literature(Angeloni et al., Ann. Chim., vol. 55, p. 1028 (1965)). A compound ofthe formula (V) wherein X=S, Y=NH, R⁵=H and R⁶=H may be synthesized bythe process described in the literature (Hansch et al., J. Org. Chem.,vol. 21, p. 265 (1956)). A compound of the formula (V) wherein X=CH₂,Y=NH, R⁵=H and R⁶=H may be synthesized by the process described in theliterature (Miller et al., J. Org. Chem., vol. 45, p. 5312 (1980)). Acompound of the formula (V) wherein X=CH₂, Y=NH, R⁵=CH₃ and R⁶=CH₃ maybe synthesized by the process described in the literature (Miller etal., Chem. Ber., vol. 23, p. 1885 (1890)). A compound of the formula (V)wherein X=CH₂, Y=NH, R⁵=CH₃ and R⁶=(4-OCH₃)phenyl may be synthesized bythe process described in the literature (Allen et al., J. Chem. Soc., p.1045 (1960)). A compound of the formula (V) wherein X=NH, Y=O, R⁵=CH₃and R⁶=(4-OCH₃)phenyl, and a compound of the formula (V) wherein X=NH,Y=O, R⁵=CH₃ and R⁶=(3-OCH₃)phenyl may be synthesized by the processdescribed in the literature (Angerer et al., J. Med. Chem., p. 1439(1984)).

The present compounds and the starting compounds and intermediates forpreparing each of the present compounds which can be obtained as setforth above may be isolated and purified by the conventional means suchas extraction, crystallization, distillation, chromatography,recrystallization or the like.

Salts of a compound of the general formula (I) may be a known salt, andexamples thereof include hydrochloride, hydrobromide, sulfate,hydrogensulfate, dihydrogen phosphate, citrate, maleate, tartrate,fumarate, gluconate, methanesulfonate and the like, and acid additionsalts with an optically active acid such as camphorsulfonic acid,mandelic acid or substituted mandelic acid. Among them, pharmaceuticallyacceptable salts are particularly preferred.

When a compound of the general formula (I) is converted into its salt,an acid addition salt of the compound can be obtained by dissolving thecompound in alcohol such as methanol or ethanol, to which the equivalentamount to several times amount of the acid component is then added. Theacid component to be used may be a pharmaceutically acceptable mineralor organic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, hydrogensulfate, dihydrogen phosphate, citric acid, maleic acid,tartaric acid, fumaric acid, gluconic acid or methanesulfonic acid.

Compounds of the present invention and pharmaceutically acceptable saltsthereof, which have no recognizable toxic effect, are useful as amedicine. For example, the compounds, which have β3-receptor agonistactivities, can be used as a medicine for treating and preventingβ3-receptor associated diseases. The term “β3-receptor associateddisease” is a generic term directed to diseases which can be improved byagonistic effects mediated by the receptor. Examples of β3-receptorassociated diseases include diabetes, obesity, hyperlipidemia, digestivediseases (preferably dyskinesiaof digestive system or ulcer), depressionand urinary disturbances.

Even compounds of the present invention and pharmaceutically acceptablesalts thereof obtained by a synthetic means have β3-receptor agonisticeffects, and those generated as a result of an in vivo metabolism alsohave the same β3-receptor agonistic effects. Therefore, compounds whichgenerate the present compound as a result of an in vivo metabolism arealso useful as a medicine.

A medicine of the present invention is preferably prepared in the formof a pharmaceutical composition by optionally adding a pharmaceuticallyacceptable carrier to an effective amount of a compound represented bythe general formula (I) or a salt thereof. Examples of pharmaceuticallyacceptable carriers include excipients, binders such ascarboxymethylcellulose, disintegrators, lubricants, auxiliaries and thelike.

When a compound of the present invention is administered to humans, itcan be orally administered in the form of tablet, powder, granule,capsule, sugar-coated tablet, solution, syrup or the like. Further, itcan be parenterally administered in the form of injection or the like.The dosage administered will vary dependent on the age and weight of thepatient and the extent of disease. The daily dosage for an adult isusually from 0.01 to 2000 mg, which is singly administered or is dividedinto several dosages and then administered. The administration periodcan vary between several weeks and several months and the everydaymedication is usually applied. However, the daily dosage andadministration period can be increased or decreased from the aboveranges dependent on the conditions of patient.

The disclosures in the text of specification and/or drawings of JapanesePatent Application No. 2000-130414, from which the present applicationclaims the priority right, are incorporated herein.

The following Examples, Reference Examples and Test Examplesspecifically illustrate this invention but are not intended to limit itin any way.

In the following examples, each analysis was carried out as follows.

(1) Fast Atom Bombardment Mass Spectrum (FAB-MS)

Fast atom bombardment mass spectrum was determined with a JMS-AX500 typemass spectrometer manufactured by JEOL. LTD (Japan) or a JMS-SX102 typemass spectrometer manufactured by JEOL. LTD (Japan). The matrix used wasm-nitrobenzyl alcohol.

(2) Liquid Chromatography-Mass Spectrometry (LC-MS)

The mass spectrometer used was a Platform-LC type mass spectrometermanufactured by Micromassm (England). A compound to be analyzed wasionized by erectrospray (ESI) method. The liquid chromatograph used wasthat manufactured by GILSON (France). The separation column used wasMightysil RP-18 GP 50-4.6 (product number 25468-96) manufactured byKANTO KAGAKU (Japan). The eluting conditions are as follows.

Flow rate: 2 mL/min;

Solvent:

-   -   Liquid A=water containing 0.1% (v/v) acetic acid;    -   Liquid B=acetonitrile containing 0.1% (v/v) acetic acid;    -   A linear gradient of 5-100% (v/v) Liquid B over 5 minutes    -   (from 0 to 5 min) was used.

Elution time was indicated by “minute”.

(3) Proton Nuclear Magnetic Resonance (¹H-NMR) Spectrum

The determination of proton nuclear magnetic resonance spectrum wascarried out using a Gemini-300 type nuclear magnetic resonance apparatusmanufactured by Varian (U.S.A.). Tetramethylsilane was used as theinternal standard and chemical shift was indicated in δ (ppm). In thisconnection, the splitting patterns were indicated using the followingabbreviations.

s: singlet; d: doublet; t: triplet; quartet: quartet; quintet: quintet;m: multiplet; dd: double doublet; dt: double triplet; brs: broadsinglet.

(4) Thin Layer Chromatography (TLC)

The thin layer chromatography (TLC) used was TLC plate (silica gel 60F₂₅₄, product number 1,05715) manufactured by Merck (Germany). Thedetection of a compound was carried out by developing the plate followedby irradiation with UV (254 nm).

(5) Preparative Liquid Chromatography

A purifying process with silica gel column was carried out using silicagel 60 manufactured by Merck (Germany). An objective compound was elutedwith a mixed solvent (n-hexane/ethyl acetate or chloroform/methanol).

A purifying process with reversed phase column was carried out using aYMC CombiPrep ODS-A CCAAS05-0520WT type column manufactured by YMC(Japan). An objective compound was eluted by gradient elution usingwater/acetonitrile (containing 0.1% (v/v) acetic acid). The detailedeluting conditions are as follows.

Flow rate: 20 mL/min;

Solvent:

-   -   Liquid A=water containing 0.1% (v/v) trifluoroacetic acid;    -   Liquid B=acetonitrile containing 0.1% (v/v) trifluoroacetic        acid;    -   From 0 to 1 min: Liquid B was maintained at 5% (v/v).    -   From 1 to 11 min: A linear gradient of 5-50% (v/v) Liquid B was        used.    -   From 11 to 16 min: A linear gradient of 50-100% (v/v) Liquid B        was used.

The following abbreviations are used in Examples set forth below.

-   -   DMSO: dimethylsulfoxide    -   THF: tetrahydrofuran    -   DMF: dimethylformamide

With respect to intermediates about which no preparing process andreference are described in Examples or Reference Examples, theirchemical names and the literatures comprising described thereinprocesses for preparing them are mentioned below.

N-(3-bromoacetylphenyl)methanesulfonamide (Larsen et al., J. Med. Chem.,vol. 9, pp. 88-97 (1966));

2-benzyloxy-5-bromoacetyl-N-methylbenzenesulfonamide (JP-A-9-249623);

N-(5-bromoacetyl-2-chlorophenyl)methanesulfonamide (JP-A-9-249623); and

N-(3-bromoacetyl-4-fluorophenyl)methanesulfonamide (WO91/12236).

EXAMPLE 1 Synthesis of 2-(2,3-dimethyl-1H-indol-6-yloxy)ethylcarbamicacid benzyl ester

2,3-Dimethyl-6-methoxy-1H-indole (2.0 g; synthesized by the processreported by Ockenden et al., J. Chem. Soc., pp. 3175-3180 (1957)) wasmixed with pyridine hydrochloride (7.91 g; mfd. by KANTO KAGAKU). Theresulting mixture was stirred at 200° C. for 15 minutes and then cooled.After adding water (100 mL), the mixture was then extracted with ethylacetate (100 mL). The organic layer was dried over anhydrous sodiumsulfate (10 g). The solvent was distilled off under reduced pressure toyield crude 2,3-dimethyl-6-hydroxy-1H-indole (1.86 g) as a gray crystal.

The thus obtained compound (200 mg), 2-bromoethylcarbamic acid benzylester (480 mg; synthesized according to the process described inJP-A-9-249623) and potassium carbonate (343 mg) were suspended in DMF (2mL), and the mixture was stirred at 80° C. for 3 hours. The reactionmixture was cooled and then poured into water (50 mL). The reactionmixture was extracted with ethyl acetate (50 mL) twice. The organiclayer was dried over anhydrous sodium sulfate (5 g) and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (99:1 chloroform/methanol) to yield the titlecompound (214 mg) as a colorless crystal.

¹H-NMR (DMSO-d₆): δ(ppm) 10.42 (1H, s), 7.49 (1H, t, J=5.3) 7.36-7.28(5H, m), 7.20 (1H, d, J=8.4), 6.74 (1H, d, J=1.8), 6.58 (1H, dd, J=2.1,8.7), 5.04 (2H, s), 3.95 (2H, t, J=5.7), 3.38 (2H, quartet, J=5.7), 2.25(3H, s), 2.10 (3H, d, J=0.6);

TLC (99:1 chloroform/methanol): R_(f)=0.34;

LC-MS: elution time 4.6 minutes;

m/z=337 (M−H)⁻.

EXAMPLE 2 Synthesis of 2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamine

The compound (202 mg; obtained in Example 1) was dissolved in ethanol (5mL) and 10% palladium/activated carbon (50 mg) was added. The resultingmixture was stirred overnight under a hydrogen gas at atmosphericpressure at room temperature. Palladium/activated carbon was filteredoff and the solvent was distilled off under reduced pressure. Theresidue was washed with isopropyl ether and dried under reduced pressureto yield the title compound (95 mg) as a colorless crystal.

¹H-NMR (DMSO-d₆): δ(ppm) 10.55 (1H, s), 8.26 (3H, brs), 7.24 (1H, d,J=8.4), 6.81 (1H, d, J=2.4), 6.65 (1H, dd, J=2.1, 8.7), 4.15 (2H, t,J=5.1), 3.19 (2H, quartet, J=5.1), 2.26 (3H, s), 2.11 (3H, s);

LC-MS: elution time 1.8 minutes;

m/z=205 (MH)⁺.

REFERENCE EXAMPLE 1 Synthesis ofN-(3-acetyl-4-chlorophenyl)methanesulfonamide

1-(5-Amino-2-chlorophenyl)ethanone (411 mg; synthesized by the processreported by Radziejewski et al., Heterocycles, vol. 26, pp. 1227-1238(1987)) was dissolved in toluene (5 mL), and pyridine (235 μL) andmethanesulfonyl chloride (225 μL) were added. The resulting mixture wasstirred at room temperature for 50 minutes. After adding water (50 mL),the reaction mixture was extracted with ethyl acetate (500 mL). Theorganic layer was washed with an aqueous 1 N hydrochloric acid solution(50 mL) and saturated brine (50 mL) and then dried over anhydrous sodiumsulfate (5 g). The solvent was distilled off under reduced pressure toyield the title compound (595 mg) as a colorless crystal.

¹H-NMR (CDCl₃): δ(ppm) 7.43-7.33 (3H, m), 7.10 (1H, brs), 3.05 (3H, s),2.67 (3H, s);

TLC (1:1 n-hexane/ethyl acetate): R_(f)=0.31;

LC-MS: elution time 3.1 minutes;

m/z=246 (M−H)⁻.

REFERENCE EXAMPLE 2 Synthesis ofN-(3-bromoacetyl-4-chlorophenyl)methanesulfonamide

The compound (300 mg; obtained in Reference Example 1) was dissolved indioxane (5 mL), and bromine (77 μL) was added dropwise with ice-cooling.After stirring at room temperature for 1 hour, the solvent was distilledoff under reduced pressure. The residue was washed with a water/ethanolmixture (1:1) and then dried under reduced pressure to yield the titlecompound (312 mg) as a colorless crystal.

¹H-NMR (CDCl₃): δ(ppm) 7.46-7.36 (3H, m), 6.90 (1H, brs), 4.52 (2H, s),3.07 (3H, s);

TLC (4:1 n-hexane/ethyl acetate): R_(f)=0.31;

LC-MS: elution time 3.5 minutes;

m/z=324 (M−H)⁻.

REFERENCE EXAMPLE 3 Synthesis ofN-(3-acetyl-5-aminophenyl)methanesulfonamide

3-Amino-5-nitrobenzophenone (4 g; synthesized by the process reported byBerend et al., J. Prakt. Chem., vol. 69, p. 471 (1904)) was dissolved inpyridine (40 mL), and the temperature was maintained at 50° C.Methanesulfonyl chloride (1.9 mL) was added, followed by stirring for 2hours. Additional methanesulfonyl chloride (1.7 mL) was added, followedby stirring at 50° C. for 2 hours. The reaction mixture was cooled downto room temperature and then poured into water (200 mL). The depositedprecipitation was collected by filtration and dried under reducedpressure to yield N-(3-acetyl-5-nitrophenyl)methanesulfonamide (5.4 g)as a crude product. The whole quantity of the crude product wasdissolved in ethanol (40 mL), and zinc dust (20 g) was added. Afterfurther adding concentrated hydrochloric acid (2 mL), the mixture washeated to reflux for 4 hours. The reaction mixture was filtered. To thefiltrate, ethyl acetate (100 mL) was added. The mixture was washed withwater (100 mL) three times and the organic layer was dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure and the residue was purified by silica gel columnchromatography (95:5 chloroform/methanol) to yield the title compound(3.9 g).

¹H-NMR (DMSO-d₆): δ(ppm) 8.27 (1H, brs), 6.96 (1H, m), 6.93 (1H, m),6.71 (1H, m);

TLC (10:1 chloroform/methanol): R_(f)=0.55;

FAB-MS: m/z=229 (M+H)⁺.

REFERENCE EXAMPLE 4 Synthesis ofN-(3-acetyl-5-chlorophenyl)methanesulfonamide

Sodium nitrite (0.34 g) was added in three portions to concentratedsulfuric acid (3.5 mL). After the addition was completed, the solutionwas stirred at 70° C. for 10 minutes to dissolve the sodium nitritecompletely. The resulting solution was allowed to cool down to roomtemperature and then a suspension of the compound (1 g; obtained inReference Example 3) in acetic acid (8 mL) was gradually added withice-cooling. The resulting mixture was allowed to stand at roomtemperature for 30 minutes and then stirred at 40° C. for 30 minutes toyield a dark red diazonium salt solution. The diazonium salt solutionwas gradually added to a solution of cuprous chloride (0.95 g) inconcentrated hydrochloric acid (10 mL) at room temperature. Afterfoaming was over, the reaction mixture was stirred at 8° C. for 30minutes and then allowed to room temperature. Water (60 mL) was addedand-the mixture was extracted with ethyl acetate (100 mL). The ethylacetate layer was washed with water (100 mL) three times and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(98:2 chloroform/methanol) to yield the title compound (350 mg) as alight brown powder.

¹H-NMR (DMSO-d₆): δ(ppm) 7.72 (1H, m), 7.68 (1H, m), 7.55 (1H, m), 3.13(3H, s), 2.61 (3H, s);

TLC (10:1 chloroform/methanol): R_(f)=0.60;

FAB-MS: m/z=249 (M+H)⁺.

REFERENCE EXAMPLE 5 Synthesis ofN-(3-acetyl-5-bromophenyl)methanesulfonamide

The procedure of Reference Example 4 was repeated using the compound (1g; obtained in Reference Example 3) as the starting material except thatcuprous bromide (1.5 g) and hydrobromic acid were used instead ofcuprous chloride and concentrated hydrochloric acid. An after-treatmentaccording to Reference Example 4 yielded the title compound (350 mg) asa colorless crystal.

¹H-NMR (DMSO-d₆): δ(ppm) 10.21 (1H, brs), 7.83 (1H, m), 7.73 (1H, m),7.60 (1H, m), 3.08 (3H, s), 2.57 (3H, s);

TLC (10:1 chloroform/methanol): R_(f)=0.86;

FAB-MS: m/z=293 (M+H)⁺.

REFERENCE EXAMPLE 6 Synthesis ofN-(3-bromoacetyl-5-chlorophenyl)methanesulfonamide

The compound (500 mg; obtained in Reference Example 4) was dissolved indioxane (10 mL). The temperature was maintained at 50° C. and bromine(0.11 mL) was added. After stirring for 30 minutes, water (50 mL) wasadded to the mixture, and the mixture was extracted with ethyl acetate(50 mL). The ethyl acetate layer was washed with water (50 mL) twice andthen dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure and the residue was purified by silica gelcolumn chromatography (1:2 ethyl acetate/hexane) to yield the titlecompound (600 mg) as a colorless crystal.

¹H-NMR (DMSO-d₆): δ(ppm) 10.29 (1H, brs), 7.80 (1H, m), 7.70 (1H, m),7.50 (1H, m), 4.92 (2H, s), 3.80 (3H, s);

TLC (1:1 n-hexane/ethyl acetate): R_(f)=0.85;

FAB-MS: m/z=328 (M+H)⁺.

REFERENCE EXAMPLE 7 Synthesis ofN-(3-bromoacetyl-5-bromophenyl)methanesulfonamide

The procedure of Reference Example 6 was repeated using the compound(650 mg; obtained in Reference Example 5) as

TABLE 1 LC-MS Amount of retention Starting compound Starting compoundtriethylamine Product LC-MS time Ex. (amount mg) (amount mg) (μL) (yieldmg) (m/e) (min) 4 N-(5-bromoacetyl-2- 2-(2,3-dimethyl- 7N-[5-[2-[2-(2,3-dimethyl-1H-indol-6- 452 2.36 chlorophenyl) 1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2- (M + H)+ methanesulfonamideyloxy)ethylamine chlorophenyl]methanesulfonamide (16 mg) (31 mg)trifluoroacetate (7.1 mg) 5 N-(3-bromoacetyl-4- 2-(2,3-dimethyl- 7N-[3-[2-[2-(2,3-dimethyl-1H-indol-6- 436 2.33 fluorophenyl) 1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-4- (M + H)+ methanesulfonamideyloxy)ethylamine fluorophenyl]methanesulfonamide (16 mg) (31 mg)trifluoroacetate (5.9 mg) 6 N-(3-bromoacetyl-4- 2-(2,3-dimethyl- 7N-[3-[2-[2-(2,3-dimethyl-1H-indol-6- 452 2.43 chlorophenyl) 1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-4- (M + H)+ methanesulfonamideyloxy)ethylamine chlorophenyl]methanesulfonamide (16 mg) (31 mg)trifluoroacetate (10.3 mg) 7 N-(5-bromoacetyl-3- 2-(2,3-dimethyl- 7N-[5-[2-[2-(2,3-dimethyl-1H-indol-6- 452 2.48 chlorophenyl) 1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-3- (M + H)+ methanesulfonamideyloxy)ethylamine chlorophenyl]methanesulfonamide (16 mg) (31 mg)trifluoroacetate (6.1 mg) 8 N-(3-bromo-5- 2-(2,3-dimethyl- 7N-[5-[2-[2-(2,3-dimethyl-1H-indol-6- 496 2.52 bromoacetylphenyl)1H-indol-6- yloxy)ethylamino]-1-hydroxyethyl]-3- (M + H)+methanesulfonamide yloxy)ethylamine bromophenyl]methanesulfonamide (19mg) (31 mg) trifluoroacetate (6.1 mg)the starting material to yield the title compound (510 mg) as alight-brown powder.

¹H-NMR (DMSO-d₆): δ(ppm) 10.26 (1H, brs), 7.91 (1H, m), 7.75 (1H, m),7.63 (1H, m), 4.91 (2H, s), 3.09 (3H, s);

TLC (1:1 n-hexane/ethyl acetate): R_(f)=0.75.

EXAMPLE 3 Synthesis ofN-[3-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidetrifluoroacetate

N-(3-Bromoacetylphenyl)methanesulfonamide (15 mg), the compound (31 mg;obtained in Example 2) and triethylamine (7 μL) were added to DMF (1 mL)and the resulting mixture was stirred at room temperature for 1 hour. Asolution of sodium borohydride (9.5 mg) in ethanol (1 mL) was thenadded, followed by stirring at room temperature for 5 hours. The solventwas distilled off under reduced pressure. The residue was washed withdilute aqueous ammonia (1 mL, 2.5% (w/v)) twice, dried under reducedpressure, and purified by reversed phase column chromatography to yieldthe title compound (4.3 mg) as a colorless crystal.

LC-MS: elution time 2.27 minutes;

m/z=418 (M+H)⁺.

According to the procedure of Example 3, the compounds (Examples 4-8) ofTable 1 were synthesized.

EXAMPLE 9 Synthesis ofN-methyl-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamidetrifluoroacetate

N-Methyl-(2-benzyloxy-5-bromoacetyl)benzenesulfonamide (20 mg), thecompound (31 mg; obtained in Example 2) and triethylamine (7 μL) wereadded to DMF (1 mL), and the resulting mixture was stirred at roomtemperature for 1 hour. A solution of sodium borohydride (9.5 mg) inethanol (1 mL) was then added, followed by stirring at room temperaturefor 5 hours. The solvent was distilled off under reduced pressure. Theresidue was washed with dilute aqueous ammonia (1 mL, 2.5% (w/v)) twice,dried under reduced pressure, and purified by reversed phase columnchromatography to yieldN-methyl-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzenesulfonamidetrifluoroacetate (16.5 mg). This compound was dissolved in DMF (0.4 mL).10% Palladium/activated carbon (10 mg) was added and the mixture wasstirred under a hydrogen gas at atmospheric pressure for 3 hours. Thepalladium/activated carbon was filtered off and the solvent was thendistilled off under reduced pressure to yield the title compound (15.3mg) as a colorless syrup.

LC-MS: elution time 2.20 minutes;

m/z=434 (M+H)⁺.

EXAMPLE 10 Synthesis of(R)-N-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

(Step A) Synthesis of(R)-N-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-triethylsilyloxyethyl]-2-chlorophenyl]methanesulfonamide

The compound (471 mg; obtained in Example 2) was dissolved inacetonitrile (16 mL), to which(R)-N-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-chlorophenyl]methanesulfonamide(960 mg; synthesized according to the process described in WO 97/25311)and potassium carbonate (540 mg) were added. The resulting mixture washeated to reflux for 20 hours. The reaction mixture was filtered and thefiltrate was placed under reduced pressure to distill the solvent off.The residue was purified by silica gel column chromatography (100:1-75:1chloroform/methanol) to yield the title compound (690 mg).

¹H-NMR (CDCl₃): δ(ppm) 0.51-0.60 (6H, m), 0.89 (9H, t, J=7.7), 2.18 (3H,s), 2.32 (3H, s), 2.74-3.01 (4H, m), 2.94 (3H, s), 3.48 (1H, s), 4.07(2H, t, J=5.1), 4.83 (1H, dd, J=4.4, 7.1), 6.67 (1H, dd, J=2.2, 8.5),6.77 (1H, d, J=2.2), 7.12-7.17 (2H, m), 7.30 (1H, d, J=8.6), 7.37 (1H,d, J=8.3), 7.64-7.66 (2H, m);

FAB-MS: m/z=566 (M+H)⁺.

(Step B) Synthesis of(R)-N-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

The compound (640 mg; obtained in the above step A) was dissolved in THF(36 mL), to which acetic acid (0.43 mL) and a solution of 1 Mtetra-n-butylammonium fluoride in THF (7.5 mL) were added. Afterstirring at room temperature for 2 hours, the reaction mixture wasdiluted with ethyl acetate, and then washed with a saturated aqueoussodium bicarbonate solution (three times) and saturated brine (threetimes). The organic layer was dried and the solvent was distilled offunder reduced pressure. The residue was dissolved in ethanol, to whichethanolic 0.5 N hydrochloric acid was added. After stirring, the solventwas distilled off under reduced pressure. To the residue, chloroform wasadded. The generated precipitate was collected by filtration and thendried to yield the title compound (381 mg).

¹H-NMR (CD₃OD): δ(ppm) 2.15 (3H, s), 2.30 (3H, s), 2.99 (3H, s),3.16-3.55 (4H, m), 4.30 (2H, t, J=6.1), 5.04 (1H, dd, J=2.9, 10.3), 6.72(1H, dd, J=2.2, 8.5), 6.87 (1H, d, J=2.2), 7.26 (1H, d, J=8.6), 7.31(1H, dd, J=2.2, 8.2), 7.51 (1H, d, J=8.3), 7.66 (1H, d, J=2.2);

FAB-MS: m/z=452 (M+H)⁺.

EXAMPLE 11 Synthesis of(R)-N-[3-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

(Step A) Synthesis of(R)-N-[3-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

The compound (233 mg; synthesized according to the procedure of the stepA of Example 10) was dissolved in ethanol (16 mL). After adding 10%palladium/carbon powder (22 mg), the resulting mixture was stirred undera hydrogen atmosphere at room temperature for 20 hours. The reactionmixture was filtered and the filtrate was placed under reduced pressureto distill the solvent off to yield the title compound (220 mg).

¹H-NMR (CDCl₃): δ(ppm) 0.50-0.59 (6H, m), 0.88 (9H, t, J=7.7), 2.18 (3H,s), 2.32 (3H, s), 2.77-3.03 (4H, m), 2.94 (3H, s), 4.08 (2H, t, J=5.1),4.85 (1H, dd, J=4.4, 7.2), 6.70 (1H, dd, J=2.0, 8.5), 6.74 (1H, d,J=2.0), 7.15-7.33 (5H, m), 7.69 (1H, brs);

FAB-MS: m/z=532 (M+H)⁺.

(Step B) Synthesis(R)-N-[3-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

The compound (220 mg; obtained in the above step A) was subjected to areaction similar to that of the step B of Example 10 to yield the titlecompound (88.3 mg).

¹H-NMR (CD₃OD): δ(ppm) 2.15 (3H, s), 2.30 (3H, s), 2.94 (3H, s),3.19-3.53 (4H, m), 4.30 (2H, t, J=6.1), 4.99-5.05 (1H, m), 6.71 (1H, dd,J=2.2, 8.5), 6.86 (1H, d, J=1.8), 7.18-7.40 (5H, m);

FAB-MS: m/z=418 (M+H)⁺.

EXAMPLE 12 Synthesis ofN-methyl-(R)-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamidehydrochloride

(Step A) Synthesis ofN-methyl-(R)-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-triethylsilyloxyethyl]-2-benzyloxy]benzenesulfonamide

The compound (306 mg; synthesized in Example 2) was dissolved inacetonitrile (10.4 mL), to whichN-methyl-(R)-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-benzyloxy]benzenesulfonamide(715 mg; synthesized according to the process described in WO 97/25311)and potassium carbonate (351 mg) were added. The resulting mixture washeated to reflux for 22 hours. The reaction mixture was filtered and thefiltrate was placed under reduced pressure to distill the solvent off.The residue was purified by silica gel column chromatography (100:1-75:1chloroform/methanol) to yield the title compound (237 mg).

¹H-NMR (CDCl₃): δ(ppm) 0.49-0.58 (6H, m), 0.87 (9H, t, J=7.5), 2.18 (3H,s), 2.31 (3H, s), 2.50 (3H, d, J=5.5), 2.75-3.00 (4H, m), 4.06 (2H, t,J=5.1), 4.67 (1H, d, J=5.3), 4.80-4.86 (1H, m), 5.19 (2H, s), 6.70-6.73(2H, m), 7.04-7.12 (1H, m), 7.25-7.55 (7H, m), 7.77 (1H, brs), 7.96 (1H,brs).

(Step B) Synthesis ofN-methyl-(R)-[5-[2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamidehydrochloride

The compound (234 mg; obtained in the above step A) was dissolved inethanol (15 mL), to which 10% palladium/carbon powder (50 mg) was added.The resulting mixture was stirred under a hydrogen atmosphere at roomtemperature for 5 hours. The reaction mixture was filtered and thesolvent contained in the filtrate was distilled off under reducedpressure. The residue was dissolved in THF (13 mL), to which acetic acid(0.15 mL) and a solution of 1 M tetra-n-butylammonium fluoride in THF(2.64 mL) were added. The resulting mixture was stirred at roomtemperature for 2 hours. The reaction mixture was diluted with ethylacetate and then washed with a saturated aqueous sodium bicarbonatesolution (four times) and saturated brine (twice). The organic layer wasdried and the solvent was distilled off under reduced pressure. Theresidue was dissolved in THF, to which ethanolic 0.5 N hydrochloric acidwas added. After stirring, the solvent was distilled off under reducedpressure. To the residue, chloroform was added. The generatedprecipitate was collected by filtration and dried to yield the titlecompound (102 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 2.10 (3H, s), 2.25 (3H, s), 2.39 (3H, s),3.00-3.50 (4H, m), 4.18-4.25 (2H, m), 4.88-4.95 (1H, m), 6.15 (1H, brs),6.60-6.68 (1H, m), 6.78-6.90 (2H, m), 7.01-7.04 (1H, m), 7.21-7.24 (1H,m), 7.43-7.67 (1H, m), 7.68-7.70 (1H, m), 10.48 (1H, s);

FAB-MS: m/z=434 (M+H)⁺.

EXAMPLE 13 Synthesis of(R)-N-[3-[2-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

(Step A) Synthesis of 6-hydroxy-3-methyl-2-phenyl-1H-indole

6-Methoxy-3-methyl-2-phenyl-1H-indole (5.00 g; synthesized according tothe process described in Tetrahedron, vol. 41, p. 4615 (1985)) andpyridine hydrochloride (11.56 g) were stirred at 180° C. for 100minutes. After the reaction mixture was cooled down to room temperature,ethyl acetate and water were added. After the layers were separated, theorganic layer was washed sequentially with aqueous 0.5 N hydrochloricacid and saturated brine, and dried. The solvent was then distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography to yield the title compound (4.50 g).

¹H-NMR (DMSO-d₆): δ(ppm) 2.36 (3H, s), 6.54 (1H, dd, J=2.2, 8.5), 6.73(1H, d, J=2.2), 7.25-7.32 (2H, m), 7.46 (2H, t, J=7.7), 7.58-7.64 (2H,m), 8.95 (1H, s), 10.74 (1H, brs).

(Step B) Synthesis of6-[2-(N-benzyloxycarbonyl)aminoethoxy]-3-methyl-2-phenyl-1H-indole

The compound (2.0 g; obtained in the above step A) was dissolved inN,N-dimethylacetamide (25 mL), to whichN-benzyloxycarbonyl-2-bromoethylamine (2.95 g; synthesized according tothe process described in JP-A-9-249623) and potassium carbonate (2.47 g)were added. The resulting mixture was stirred at 70° C. for 15.5 hours.After adding water, the reaction mixture was extracted with ether. Theorganic layer was washed with water and saturated brine and then dried.The solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (99:1 chloroform/methanol)to yield the title compound (2.0 g).

¹H-NMR (DMSO-d₆): δ(ppm) 2.38 (3H, s), 3.41 (2H, m), 4.01 (2H, t,J=5.5), 5.05 (2H, s), 6.67 (1H, dd, J=2.2, 8.5), 6.84 (1H, d, J=2.2),7.28-7.52 (9H, m), 7.61-7.65 (2H, m), 10.97 (1H, brs).

(Step C) Synthesis of 6-(2-aminoethoxy)-3-methyl-2-phenyl-1H-indole

The compound (2.0 g; obtained in the above step B) was dissolved in asolution of 30% hydrobromic acid in acetic acid (25 mL), followed bystirring at room temperature for 3 hours. The reaction mixture wasdiluted with ether and neutralized with an aqueous 5 N sodium hydroxidesolution. The organic layer was washed with water and saturated brineand then dried. The solvent was distilled off under reduced pressure toyield the title compound (1.06 g).

¹H-NMR (DMSO-d₆): δ(ppm) 2.39 (3H, s), 3.25 (2H, m), 4.18 (2H, t,J=5.5), 6.75 (1H, dd, J=2.2, 8.5), 6.91 (1H, d, J=2.2), 7.25-7.68 (6H,m), 8.05 (2H, brs), 11.05 (1H, brs).

(Step D) Synthesis of(R)-N-[3-[2-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

The compound (400 mg; obtained in the above step C) was dissolved inN,N-dimethylacetamide (5 mL), to which(R)-N-[3-(2-iodo-1-triethylsilyloxyethyl)phenyl]methanesulfonamide (752mg) and diisopropylethylamine (640 mg) were added. The resulting mixturewas stirred at 70° C. for 20 hours. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The organic layer waswashed with water and saturated brine and then dried. The solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (99:1-95:5 chloroform/methanol) to yield thetitle compound (110 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 0.47-0.56 (6H, m), 0.85 (9H, t, J=8.2), 2.38(3H, s), 2.65-2.79 (2H, m), 2.86-2.98 (2H, m), 2.94 (3H, s), 4.00-4.06(2H, m), 4.76-4.80 (1H, m), 6.65 (1H, dd, J=2.2, 8.5), 6.83 (1H, d,J=2.2), 7.03-7.15 (2H, m), 7.25-7.35 (4H, m), 7.39 (1H, d, J=8.5), 7.49(2H, t, J=7.7), 7.60-7.64 (2H, m), 9.74 (1H, brs), 10.95 (1H, brs).

(Step E) Synthesis of(R)-N-[3-[2-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

The compound (110 mg; obtained in the above step D) was dissolved in THF(1 mL), to which tetra-n-butylammonium fluoride (370 μL, 1 M THFsolution) and acetic acid (21 μL) were added. After stirring at roomtemperature for 4 hours, the reaction mixture was purified by PTLC (4:1chloroform/methanol). The thus obtained crude product was dissolved inether. Ethanolic 0.5 N hydrochloric acid was added, followed bystirring. The generated precipitate was collected by filtration anddried to yield the title compound (33.9 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 2.39 (3H, s), 3.00 (3H, s), 3.02-3.16 (2H, m),3.22-3.34 (2H, m), 4.30-4.36 (2H, m), 4.96-5.04 (1H, m), 6.25 (1H, brs),6.75 (1H, dd, J=2.2, 8.5), 6.91 (1H, d, J=2.2), 7.11-7.18 (2H, m),7.30-7.53 (6H, m), 7.61-7.67 (2H, m), 8.90 (1H, brs), 9.09 (1H, brs),9.85 (1H, s), 11.06 (1H, brs).

EXAMPLE 14 Synthesis of(R)-N-[3-[2-[2-(2,3-diphenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

(Step A) Synthesis of 6-(2-aminoethoxy)-2,3-diphenyl-1H-indole

6-Hydroxy-2,3-diphenyl-1H-indole (2.50 g; synthesized according to theprocess described in J. Chem. Soc., p. 5097 (1957)) was dissolved inN,N-dimethylacetamide (20 mL), to whichN-benzyloxycarbonyl-2-bromoethylamine (2.93 g; synthesized according tothe process described in WO 97/25311) and potassium carbonate (2.42 g)were added. After stirring at 70° C. for 14.5 hours, the reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and then dried. Thesolvent was distilled off under reduced pressure. The residue waspurified twice by silica gel column chromatography (9:1-1:1 hexane/ethylacetate) to yield a compound (900 mg) as a brown amorphous solid. Thiswas dissolved in a solution of 30% hydrobromic acid in acetic acid (10mL), followed by stirring at room temperature for 1 hour. Ether (100 mL)was added to the reaction mixture and the generated precipitate wasfiltered. The compound obtained by filtration was dissolved in ethylacetate. The thus obtained solution was washed with a saturated aqueoussodium bicarbonate solution and saturated brine and then dried. Thesolvent was distilled off under reduced pressure to yield the titlecompound (630 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 1.99 (2H, brs), 2.92 (2H, t, J=5.8), 3.96 (2H,t, J=5.8), 6.72 (1H, dd, J=2.2, 8.5), 6.92 (1H, d, J=2.2), 7.24-7.43(11H, m), 11.36 (1H, brs).

(Step B) Synthesis of(R)-N-[3-[2-[2-(2,3-diphenyl-1H-indol-6-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

The compound (328 mg; obtained in the above step A) was dissolved inN,N-dimethylacetamide (3.5 mL), to which(R)-N-[3-(2-iodo-1-triethylsilyloxyethyl)phenyl]methanesulfonamide (592mg; synthesized according to the process described in WO 97/25311) anddiisopropylethylamine (504 mg) were added. After stirring at 70° C. for14.5 hours, the reaction mixture was diluted with water and extractedwith ethyl acetate. The organic layer was washed with saturated brineand then dried. The solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (100:0-99:1chloroform/methanol) to yield the title compound (257.8 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 0.47-0.56 (6H, m), 0.85 (9H, t, J=7.7),2.66-2.81 (2H, m), 2.86-2.98 (2H, m), 2.94 (3H, s), 4.02-4.10 (2H, m),4.76-4.81 (1H, m), 6.69 (1H, dd, J=1.9, 7.9), 6.91 (1H, d, J=1.9), 7.10(2H, dd, J=1.9, 7.9), 7.24-7.44 (14H, m), 9.70 (1H, brs), 11.35 (1H,brs).

(Step C) Synthesis of(R)-N-[3-[2-[2-(2,3-diphenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

The compound (218 mg; obtained in the above step B) was dissolved in THF(2 mL), to which tetra-n-butylammonium fluoride (665 μL, 1 M THFsolution) and acetic acid (38 μL) were added. After stirring at roomtemperature for 105 minutes, the reaction mixture was purified by PTLC(Preparative TLC; mfd. by Merck) (5:1 chloroform/10% concentratedammonia water-containing methanol). The thus obtained crude product wasdissolved in ether, to which ethanolic 0.1 N hydrochloric acid (3.0 mL)was added. After stirring, the solvent was distilled off under reducedpressure. Ether was added to the residue, followed by stirring. Thegenerated precipitate was collected by filtration and dried to yield thetitle compound (125 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 3.00 (3H, s), 3.04-3.54 (4H, m), 4.32-4.38 (2H,m), 4.99-5.06 (1H, m), 6.27 (1H, brs), 6.79 (1H, dd, J=2.2, 8.5), 7.00(1H, d, J=2.2), 7.12-7.18 (2H, m), 7.26-7.46 (13H, m), 8.97 (1H, brs),9.20 (1H, brs), 9.86 (1H, s), 11.49 (1H, brs).

EXAMPLE 15 Synthesis of(R)-N-[3-[2-[2-(2-tert-butyl-3-methyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

(Step A) Synthesis of 2-tert-butyl-6-methoxy-3-methyl-1H-indole

2-Bromo-5-methoxyaniline (1.01 g; synthesized according to the processreported by J. H. Tidwell et al., J. Am. Chem. Soc., vol. 116, pp.11797-11810 (1994)), 2,2-dimethyl-3-pentyne (480 mg; mfd. byChemsampco), palladium acetate (28.1 mg), tetra-n-butylammonium chloride(1.39 g; mfd. by TOKYO KASEI), potassium carbonate (3.45 g) andtriphenylphosphine (65.6 mg) were dissolved in N,N-dimethylacetamide (50mL). After stirring at 100° C. for 20 hours, the reaction mixture wasdiluted with water and extracted with ether. The organic layer waswashed with a saturated aqueous ammonium chloride solution and water,and then dried. The solvent was distilled off under reduced pressure.The residue was purified twice by silica gel column chromatography (5:1hexane/ethyl acetate) to yield the title compound (202 mg).

¹H-NMR (CDCl₃): δ(ppm) 1.38 (9H, s), 2.27 (3H, s), 3.72 (3H, s), 6.57(1H, dd, J=2.2, 8.5), 6.78 (1H, d, J=2.2), 7.23 (1H, d, J=8.5), 10.19(1H, brs).

(Step B) Synthesis of 2-tert-butyl-6-hydroxy-3-methyl-1H-indole

The compound (200 mg; obtained in the above step A) was dissolved indehydrated methylene chloride (5 mL), followed by stirring under anargon atmosphere at 0° C. A solution of 1 N boron tribromide inmethylene chloride (5 mL) was added dropwise. The resulting mixture wasstirred for 2 hours while the temperature was gradually cooled down toroom temperature. The reaction mixture was cooled with ice. Water (10mL) was added dropwise with vigorous stirring. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with saturated brine and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (5:1-4:1 hexane/ethyl acetate) to yield the titlecompound (170 mg).

¹H-NMR (CDCl₃): δ(ppm) 1.43 (9H, s), 2.35 (3H, s), 4.62 (1H, brs), 6.63(1H, dd, J=2.2, 8.5), 6.75 (1H, d, J=2.2), 7.31 (1H, d, J=8.5), 7.67(1H, brs).

(Step C) Synthesis of(R)-2-[N′-benzyl-N′-[2-(2-tert-butyl-3-methyl-1H-indol-6-yloxy)ethyl]amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol

(R)-2-[N′-Benzyl-N′-(2-hydroxyethyl)amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol(173 mg; synthesized according to the process described in WO 01/04092)and triphenylphosphine (103 mg) were dissolved in dehydrated methylenechloride (5 mL), followed by stirring at −20° C. N-Bromosuccinimide(69.9 mg) was added at a stretch and the resulting mixture was stirredfor 10 minutes. The reaction mixture was purified by silica gel columnchromatography (5:1-3:1 hexane/ethyl acetate) to yield(R)-2-[N′-benzyl-N′-(2-bromoethyl)amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol.This was immediately dissolved in acetonitrile (2.5 mL). The compound(79.8 mg; obtained in the above step B) and an aqueous 1 N sodiumhydroxide solution (392 μL) were added, followed by stirring at roomtemperature for 14 hours. The reaction mixture was concentrated and theresidue was purified by silica gel column chromatography (4:1-2:1hexane/ethyl acetate) to yield the title compound (132.2 mg).

¹H-NMR (CDCl₃): δ(ppm) 1.43 (9H, s), 2.36 (3H, s), 2.55-2.84 (2H, m),2.86 (3H, s), 2.90-3.14 (2H, m), 3.67 (1H, d, J=13.5), 3.93 (1H, d,J=13.5), 4.06 (2H, t, J=6.0), 4.65 (1H, dd, J=3.3, 10.1), 4.77 (2H, s),6.75 (1H, dd, J=2.2, 8.5), 6.82 (1H, d, J=2.2), 7.07-7.37 (15H, m), 7.87(1H, brs).

(Step D) Synthesis of(R)-N-[3-[2-[2-(2-tert-butyl-3-methyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

The compound (100 mg; obtained in the above step C) was dissolved in amixed solvent of THF (1 mL) and methanol (1 mL), to which 20% palladiumhydroxide/carbon powder (40 mg, 50% moisture) was added. The atmospherein the system was replaced with hydrogen, followed by stirring at roomtemperature for 20 hours. The reaction mixture was filtered and thefiltrate was placed under reduced pressure to distill the solvent off.To the residue, ethanolic 0.1 N hydrochloric acid (16 mL) was added.After stirring at room temperature for 10 minutes, the solvent wasdistilled off. Ether was added to the residue. The deposited crystal wascollected by filtration and dried to yield the title compound (76.6 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 1.39 (9H, s), 2.28 (3H, s), 3.00 (3H, s),3.00-3.30 (2H, m), 3.40-3.50 (2H, m), 4.25-4.29 (2H, m), 4.98-5.11 (1H,m), 6.20 (1H, brs), 6.66 (1H, dd, J=2.2, 8.5), 6.84 (1H, d, J=2.2),7.11-7.18 (2H, m), 7.26-7.38 (3H, m), 8.91 (1H, brs), 9.15 (1H, brs),9.85 (1H, brs), 10.29 (1H, brs).

EXAMPLE 16 Synthesis of(R)-N-[3-[2-[2-(2-methyl-3-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

(Step A) Synthesis of 3-bromo-2-methoxycarbonyl-6-methoxy-1H-indole

2-Methoxycarbonyl-6-methoxy-1H-indole (1.00 g; mfd. by Aldrich) wasdissolved in DMF (51.2 mL) under an argon atmosphere, followed bystirring at 0° C. A solution of N-bromosuccinimide (1.02 g) in DMF (21.7mL) was added dropwise over 30 minutes. The reaction mixture wasmaintained at 0° C. and stirred for 2.5 hours. The reaction mixture waspoured into an ice water. After stirring, the resulting mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and saturated brine, andthen dried. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (4:1-3:1hexane/ethyl acetate) to yield the title compound (760 mg).

¹H-NMR (CDCl₃): δ(ppm) 3.86 (3H, s), 3.97 (3H, s), 6.79 (1H, d, J=2.2),6.89 (1H, dd, J=2.2, 8.8), 7.53 (1H, d, J=8.8), 8.87 (1H, brs).

(Step B) Synthesis of 2-methoxycarbonyl-6-methoxy-3-phenyl-1H-indole

The compound (700 mg; obtained in the above step A) was dissolved intoluene (10 mL). Phenylboric acid (1.43 g; mfd. by Aldrich), potassiumcarbonate (649 mg) and tetrakis(triphenylphosphine)palladium(0) (271.3mg; mfd. by Nacalai Tesque) were added and the resulting mixture washeated to reflux for 5 hours. The reaction mixture was diluted withethyl acetate and was quenched with a mixture of 30% hydrogen peroxidesolution (5 mL) and water (100 mL). The organic layer was washed with asaturated aqueous sodium bicarbonate solution and saturated brine, andthen dried. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (5:1-2:1hexane/ethyl acetate) to yield the title compound (560 mg).

¹H-NMR (CDCl₃): δ(ppm) 3.80 (3H, s), 3.88 (3H, s), 6.81 (1H, dd, J=2.2,8.5), 6.85 (1H, d, J=2.2), 7.35-7.57 (6H, m), 8.82 (1H, brs).

(Step C) Synthesis of 2-hydroxymethyl-6-methoxy-3-phenyl-1H-indole

The compound (560 mg; obtained in the above step B) was dissolved indehydrated THF(20 mL). Lithium aluminium hydride (151 mg) was added andthe resulting mixture was stirred at 40° C. for 90 minutes. Aftergradually adding an aqueous 1 N sodium hydroxide solution, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine. The solvent was distilled off under reducedpressure to yield the title compound (1.40 g).

¹H-NMR (CDCl₃): δ(ppm) 1.90 (1H, t, J=5.8), 3.86 (3H, s), 4.88 (2H, d,J=5.8), 6.81 (1H, dd, J=2.2, 8.5), 6.87 (1H, d, J=2.2), 7.29-7.36 (1H,m), 7.42-7.48 (4H, m), 7.58 (1H, d, J=8.5), 8.40 (1H, brs).

(Step D) Synthesis of 2-methyl-6-methoxy-3-phenyl-1H-indole

The compound (253.3 mg; obtained in the above step C) was dissolved indehydrated dioxane (12 mL). After adding lithium aluminium hydride (379mg), the resulting mixture was stirred at 100° C. for 47 hours. Thereaction mixture was allowed to cool down to room temperature, and thengradually added dropwise to ice water. An aqueous 5 N sodium hydroxidesolution (100 mL) was added, followed by extraction with ether. Theorganic layer was washed with saturated brine and then dried. Thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (5:1-1:1 hexane/ethylacetate) to yield the title compound (146 mg).

¹H-NMR (CDCl₃): δ(ppm) 2.48 (3H, s), 3.86 (3H, s), 6.78 (1H, dd, J=2.2,8.5), 6.85 (1H, d, J=2.2), 7.26-7.32 (1H, m), 7.42-7.55 (5H, m), 7.81(1H, brs).

(Step E) Synthesis of 6-hydroxy-2-methyl-3-phenyl-1H-indole

The compound (146 mg; obtained in the above step D) was dissolved indehydrated methylene chloride (5 mL) under an argon atmosphere, followedby stirring at 0° C. A solution of 1 M boron tribromide in methylenechloride (2 mL) was added. The resulting mixture was stirred for 3.5hours while the temperature was gradually allowed to cool down to roomtemperature. The reaction mixture was cooled with ice and water (20 mL)was gradually added dropwise. The mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and thendried. The solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (5:1-3:1 hexane/ethylacetate) to yield the title compound (116 mg).

¹H-NMR (CDCl₃): δ(ppm) 2.46 (3H, s), 4.77 (1H, brs), 6.66 (1H, dd,J=2.2, 8.5), 6.79 (1H, d, J=2.2), 7.24-7.32 (1H, m), 7.41-7.51 (5H, m),7.81 (1H, brs).

(Step F) Synthesis of(R)-2-[N′-benzyl-N′-[2-(2-methyl-3-phenyl-1H-indol-6-yloxy)ethyl]amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol

(R)-2-[N′-Benzyl-N′-(2-hydroxyethyl)amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol(273 mg; synthesized according to the process described in WO 01/04092)and triphenylphosphine (162 mg) were dissolved in dehydrated methylenechloride (8 mL) under an argon atmosphere, followed by stirring at −20°C. After adding N-bromosuccinimide (110 mg) at a stretch, the resultingmixture was stirred for 10 minutes. The reaction mixture was purified bysilica gel column chromatography (5:1-3:1 hexane/ethyl acetate) to yield(R)-2-[N′-benzyl-N′-(2-bromoethyl)amino])-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol.This was immediately dissolved in acetonitrile (4 mL), to which thecompound (116 mg; obtained in the above step E) and an aqueous 1 Nsodium hydroxide solution (521 μL) were added. The resulting mixture wasstirred at room temperature for 16 hours and the reaction mixture wasthen concentrated. The residue was purified by silica gel columnchromatography (5:1-1:1 hexane/ethyl acetate) to yield the titlecompound (243 mg).

¹H-NMR (CDCl₃): δ(ppm) 2.44 (3H, s), 2.55-2.63 (1H, m), 2.77-2.83 (1H,m), 2.87 (3H, s), 2.91-2.99 (1H, m), 3.04-3.12 (1H, m), 3.67 (1H, d,J=13.7), 3.93 (1H, d, J=13.7), 4.06 (2H, d, J=6.3), 4.65 (1H, dd, J=3.3,9.9), 4.77 (2H, s), 6.77 (1H, dd, J=2.2, 8.5), 6.85 (1H, d, J=2.2),7.08-7.12 (1H, m), 7.16-7.34 (15H, m), 7.41-7.54 (4H, m), 8.10 (1H,brs).

(Step G) Synthesis of(R)-N-[3-[2-[2-(2-methyl-3-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

The compound (135 mg; obtained in the above step F) was dissolved in amixed solvent of THF (2 mL) and methanol (2 mL), to which 20% palladiumhydroxide/carbon powder (67.5 mg; 50% moisture) was added. Theatmosphere in the system was replaced with hydrogen, followed bystirring at room temperature for 19 hours. The reaction mixture wasfiltered and the filtrate was placed under reduced pressure to distillthe solvent off. To the residue, ethanolic 0.1 N hydrochloric acid (20.4mL) was added. After stirring at room temperature for 10 minutes, thesolvent was distilled off. Ether was added to the residue. The depositedcrystal was collected by filtration and dried to yield the titlecompound (69.1 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 2.44 (3H, s), 3.00 (3H, s), 3.00-3.48 (4H, m),4.27-4.34 (2H, m), 4.95-5.02 (1H, m), 6.26 (1H, brs), 6.74 (1H, dd,J=2.2, 8.5), 6.91 (1H, d, J=2.2), 7.12-7.17 (2H, m), 7.23-7.47 (7H, m),8.88 (1H, brs), 9.03 (1H, brs), 9.85 (1H, brs), 11.06 (1H, brs).

EXAMPLE 17 Synthesis of(R)-N-[5-[2-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

(Step A) Synthesis of(R)-N-[5-[2-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamino]-1-triethylsilyloxyethyl]-2-chlorophenyl]methanesulfonamide

The compound (266 mg; obtained in the step C of Example 13) wasdissolved in acetonitrile (5 mL). After adding(R)-N-[5-(2-iodo-1-triethylsilyloxyethyl)-2-chlorophenyl]methanesulfonamide(490 mg; synthesized according to the process described in WO 97/25311)and diisopropylethylamine (646 mg), the resulting mixture was stirred at80° C. for 16.5 hours. The reaction mixture was diluted with water andthen extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and then dried. The solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (99:1 chloroform/methanol) to yield the title compound(99 mg).

¹H-NMR (CDCl₃): δ(ppm) 0.52-0.60 (6H, m), 0.89 (9H, t, J=7.9), 2.43 (3H,s), 2.75-2.91 (2H, m), 2.95 (3H, s), 3.01 (2H, t, J=5.2), 4.10 (2H, t,J=5.2), 4.83 (1H, m), 6.77 (1H, dd, J=2.2, 8.5), 6.86 (1H, d, J=2.2),7.15 (1H, dd, J=2.2, 8.5), 7.29-7.38 (2H, m), 7.43-7.58 (5H, m), 7.67(1H, d, J=2.2), 8.05 (1H, brs).

(Step B) Synthesis of(R)-N-[5-[2-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

The compound (99 mg; obtained in the above step A) was reacted accordingto the procedure of the step E of Example 13 to yield the title compound(50 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 2.39 (3H, s), 3.06 (3H, s), 3.04-3.52 (4H, m),4.29-4.36 (2H, m), 5.00-5.08 (1H, m), 6.36 (1H, m), 6.75 (1H, dd, J=2.2,8.5), 6.91 (1H, d, J=2.2), 7.28-7.36 (2H, m), 7.43-7.65 (7H, m), 8.96(1H, brs), 9.03 (1H, brs), 9.55 (1H, s), 11.05 (1H, s).

EXAMPLE 18 Synthesis of(R)-N-[3-[2-[2-(2,3-dimethylbenzofuran-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

(Step A) Synthesis of6-[2-(N-benzyloxycarbonyl)aminoethoxy]-2,3-dimethylbenzofuran

6-Hydroxy-2,3-dimethylbenzofuran (324 mg; synthesized according to theprocess described in J. Heterocyclic Chem., vol. 36, p. 509 (1999)),N-benzyloxycarbonyl-2-bromoethylamine (516 mg; synthesized according tothe process described in WO 97/25311) and potassium carbonate (691 mg)were reacted according to the procedure of the step B of Example 13 toyield the title compound (398 mg).

¹H-NMR (CDCl₃): δ(ppm) 2.10 (3H, s), 2.33 (3H, s), 3.59 (2H, quartet,J=5.2), 4.03 (2H, t, J=4.9), 5.10 (2H, s), 5.29 (1H, brs), 6.78 (1H, dd,J=2.2, 8.2), 6.88 (1H, d, J=2.2), 7.23 (1H, d, J=8.2), 7.24-7.36 (5H,m).

(Step B) Synthesis of 6-(2-aminoethoxy)-2,3-dimethylbenzofuranhydrobromide

The compound (393 mg; obtained in the above step A) was dissolved in asolution of 30% hydrobromic acid in acetic acid (5 mL), followed bystirring at room temperature for 2.5 hours. Ether was added to thereaction mixture. The generated precipitate was collected by filtration,washed with ether and dried to yield the title compound (255 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 2.10 (3H, s), 2.33 (3H, s), 3.20-3.30 (2H, m),4.17 (2H, t, J=4.9), 6.89 (1H, dd, J=2.2, 8.5), 7.13 (1H, d, J=2.2),7.37 (1H, d, J=8.5), 7.97 (3H, brs).

(Step C) Synthesis of(R)-N-[3-[2-[2-(2,3-dimethylbenzofuran-6-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

The compound (143 mg; obtained in the above step B),(R)-N-[3-(2-iodo-1-triethylsilyloxyethyl)phenyl]methanesulfonamide (227mg; synthesized according to the process described in WO 97/25311) anddiisopropylethylamine (323 mg) were reacted according to the procedureof the step D of Example 13 to yield the title compound (38.9 mg).

¹H-NMR (CDCl₃): δ(ppm) 0.50-0.61 (6H, m), 0.88 (9H, t, J=7.9), 2.11 (3H,s), 2.34 (3H, s), 2.74-3.06 (4H, m), 2.96 (3H, s), 4.08 (2H, t, J=5.2),4.81-4.86 (1H, m), 6.79 (1H, dd, J=2.2, 8.5), 6.90 (1H, d, J=2.2),7.13-7.34 (5H, m).

(Step D) Synthesis of(R)-N-[3-[2-[2-(2,3-dimethylbenzofuran-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

The compound (38.9 mg; obtained in the above step C) was reactedaccording to the procedure of the-step E of Example 13 to yield thetitle compound (14.8 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 2.10 (3H, s), 2.34 (3H, s), 3.00 (3H, s),3.00-3.46 (4H, m), 4.28-4.34 (2H, m), 4.92-4.99 (1H, m), 6.20-6.24 (1H,m), 6.89 (1H, dd, J=2.2, 8.5), 7.11-7.17 (3H, m), 7.29-7.39 (3H, m),8.87 (2H, brs), 9.84 (1H, s).

EXAMPLE 19 Synthesis of(R)-N-[3-[2-[2-(2,3-dimethylbenzothiophen-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

(Step A) Synthesis of6-[2-(N-benzyloxycarbonyl)aminoethoxy]-2,3-dimethylbenzothiophene

6-Hydroxy-2,3-dimethylbenzothiophene (356 mg; synthesized according tothe process described in Phosphorus, Sulfur and Silicon, vol. 153-154,p. 397 (1999)), N-benzyloxycarbonyl-2-bromoethylamine (516 mg;synthesized according to the process described in WO 97/25311) andpotassium carbonate (691 mg) were reacted according to the procedure ofthe step B of Example 13 to yield the title compound (356 mg).

¹H-NMR (CDCl₃): δ(ppm) 2.25 (3H, s), 2.43 (3H, s), 3.62 (2H, quartet,J=5.2), 4.07 (2H, t, J=4.9), 5.11 (2H, s), 5.26 (1H, brs), 6.93 (1H, dd,J=2.2, 8.5), 7.20 (1H, d, J=2.2), 7.28-7.38 (5H, m), 7.44 (1H, d,J=8.5).

(Step B) Synthesis of 6-(2-aminoethoxy)-2,3-dimethylbenzothiophenehydrobromide

The compound (356 mg; obtained in the above step A) was reactedaccording to the procedure of the step B of Example 18 to yield thetitle compound (237 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 2.23 (3H, s), 2.41 (3H, s), 3.20-3.30 (2H, m),4.21 (2H, t, J=4.9), 7.03 (1H, dd, J=2.5, 8.8), 7.50 (1H, d, J=2.5),7.57 (1H, d, J=8.8), 7.97 (3H, brs).

(Step C) Synthesis of(R)-N-[3-[2-[2-(2,3-dimethylbenzothiophen-6-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

The compound (151 mg; obtained in the above step B),(R)-N-[3-(2-iodo-1-triethylsilyloxyethyl)phenyl]methanesulfonamide (227mg; synthesized according to the process described in WO 97/25311) anddiisopropylethylamine (323 mg) were reacted according to the procedureof the step D of Example 13 to yield the title compound (41.6 mg).

¹H-NMR (CDCl₃): δ(ppm) 0.50-0.59 (6H, m), 0.88 (9H, t, J=7.7), 2.25 (3H,s), 2.43 (3H, s), 2.74-3.05 (4H, m), 3.01 (3H, s), 4.10 (2H, t, J=5.2),4.81-4.85 (1H, m), 6.92 (1H, dd, J=2.2, 8.5), 7.13-7.34 (5H, m), 7.44(1H, d, J=8.5).

(Step D) Synthesis of(R)-N-[3-[2-[2-(2,3-dimethylbenzothiophen-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

The compound (41.6 mg; obtained in the above step C) was reactedaccording to the procedure of the step E of Example 13 to yield thetitle compound (15.6 mg).

¹H-NMR (DMSO-d₆): δ(ppm) 2.24 (3H, s), 2.41 (3H, s), 2.96-3.48 (4H, m),3.00 (3H, s), 4.32-4.38 (2H, m), 4.92-5.00 (1H, m), 6.21-6.26 (1H, m),7.03 (1H, dd, J=2.2, 8.5), 7.11-7.17 (2H, m), 7.29-7.31 (1H, m), 7.35(1H, t, J=7.7), 7.51 (1H, d, J=2.2), 7.57 (1H, d, J=8.8), 8.90 (2H,brs), 9.84 (1H, brs).

Further, the other compounds listed in Table 2 can be also prepared byrepeating the procedures described in the present specification usingthe intermediates described in WO 97/25311 and WO 01/04092.

TABLE 2 (I)

Example No. R¹ R² Y X R⁵ R⁶ 20 Cl NHSO₂CH₃ O NH CH₃ Ph 21 Cl NHSO₂CH₃ ONH CH₃ tBu 22 Cl NHSO₂CH₃ O NH Ph CH₃ 23 Cl NHSO₂CH₃ O O CH₃ CH₃ 24 ClNHSO₂CH₃ O S CH₃ CH₃ 25 F NHSO₂CH₃ O NH CH₃ CH₃ 26 F NHSO₂CH₃ O NH CH₃Ph 27 F NHSO₂CH₃ O NH Ph CH₃ 28 F NHSO₂CH₃ O O CH₃ CH₃ 29 F NHSO₂CH₃ O SCH₃ CH₃ 30 OH SO₂NHCH₃ O NH CH₃ Ph 31 OH SO₂NHCH₃ O NH Ph CH₃ 32 OHSO₂NHCH₃ O O CH₃ CH₃ 33 OH SO₂NHCH₃ O S CH₃ CH₃ 34 H NHSO₂CH₃ O NH CH₃4-OMe—Ph 35 H NHSO₂CH₃ O NH CH₃ 3-OMe—Ph 36 H NHSO₂CH₃ O NH CH₂CH₃4-OMe—Ph 37 H NHSO₂CH₃ O NH CH₃ 4-OH—Ph 38 H NHSO₂CH₃ O NH CH₃ 3-OH—Ph39 H NHSO₂CH₃ O NH CH₂CH₃ 4-OH—Ph

TEST EXAMPLE 1 Human β3-Agonist Activities

Human β3-agonist activities were determined using CHO (Chinese hamsterovary) cells transfected with pcDNA3 (mfd. by Invitrogen) to which humanβ3 gene had been inserted. Human β3 fragment was first obtained fromhuman adipose tissue cDNA (mfd. by Clonetech) by PCR using the primer ofβ3 (Krief, et al., J. Clin. Invest., vol. 91, pp. 344-349 (1993)). Thehuman β3 fragment thus obtained was used as a probe to obtain the fulllength human β3 gene from a human genomic library (mfd. by Clonetech).The above cells were cultured in a Ham F-12 medium supplemented with 10%fetal bovine serum, 400 μg/mL geneticin (Gibco BRL), 100 U/mL penicillinand 100 μg/mL streptomycin. After placing these cells (5×10⁵) into a6-well plate and culturing them for 24 hours, they were allowed to standon a serum-free Ham F-12 medium for 2 hours. The compound was firstdissolved in DMSO, diluted to a concentration of 10⁻⁶ M with Ham F-12supplemented with 1 mM isobutylmethylxanthine and 1 mM ascorbic acid,and then added to the cells. After the cells were cultured for 30minutes, the medium was removed, followed by addition of 0.5 mL of 1 NNaOH. The medium was allowed to stand for 20 minutes and then 0.5 mL of1 N acetic acid was added to the medium. The medium was stirred andcentrifuged, followed by quantitating cAMP with cAMP EIA kit (mfd. byCayman). With respect to eight compounds among the compounds describedin Examples, their relative activities (%) as compared withisoproterenol were indicated in Table 3. Isoproterenol was purchasedfrom RBI (Research Biochemicals International). The results from Table 3indicate that the compounds of the present invention have humanβ3-agonist activities.

TEST EXAMPLE 2 Action on the Heart

The heart was excised from a male guinea pig weighing 180-250 g toprepare a specimen of the right atrium. The specimen was set in an organbath filled with a Krebs solution which had been aerated with a mixedgas of 5% CO₂/95% O₂. The automaticity was determined using a isometrictransducer (NIHON KOHDEN TB-611T) connected to a polygraph (NIHON KOHDENMR-6000). At a concentration of 10⁻⁶ M, the present compounds describedin Examples had no actions on the automaticity of the right atriumspecimen. Therefore, these compounds were expected to have selectiveactions and hardly induce an increase of the heart rate, that is, toentail few side effects.

TEST EXAMPLE 3 Pharmacological Effect on a Transgenic Mouse ExpressingHuman β3

Since β3 is species-specific (Strosberg, et al., Trends Pharmacol. Sci.,vol. 17, pp. 373-381 (1996); Strosberg, et al., Annu. Rev. Pharmacol.Toxicol., vol. 37, pp. 421-450 (1997)), pharmacological tests using atransgenic mouse expressing human β3 are more effective than those usinga normal mouse or rat. Ito, et al. prepared a replacement mouseexpressing human β3 in its brown fat by introducing human β3 gene into amouse whose mouse β3 gene had been knocked out (Ito, et al., Diabetes,vol. 47, pp. 1464-1471 (1998)). A compound of the present invention canbe tested for antiobestic activity and antidiabetic activity using atransgenic mouse according to the following procedures.

The lipolytic activity can be examined in vitro according to the methodreported by Rodbell (J. Biol. Chem., vol. 239, pp. 375-380 (1964))wherein the method comprises gathering an epididymis white adiposetissue or the like from a transgenic mouse; preparing a suspension ofthe cell in Krebs-Ringer buffer solution containing 4% bovine serumalbumin at the cell density of 2×10⁵ cell/mL; putting 300 μL aliquots ofthe suspension into separate Eppendorf tubes; adding into separatetubes, 300 μL aliquots of a medium comprising dissolved therein acompound to be tested; maintaining the temperature at 37° C. for 1 hourwhile shaking; quenching the stimulation with ice cooling; removingadipocytes with an aspirator after centrifugation; and quantifying freeglycerol with F-kit glycerol (Boehringer Mannheim).

The hypoglycemic effect can be examined as follows. After fasted forfour hours, a transgenic mouse is orally dosed with a test compounddissolved in 10% hydroxypropyl-β-cyclodextrin (Aldrich) at a dose of 0.1mL/10 g body weight. After 0 minute, 30 minutes, 1 hour and 2 hours,blood samples are collected from venous plexus of the eyeground.

The glucose tolerance can be examined as follows. After fastedovernight, a transgenic mouse is intraperitoneally dosed with glucose(Wako Pure Chemical Industries) at a dose of 1.5 g/kg and orally dosedwith a test compound dissolved in 10% hydroxypropyl-β-cyclodextrin(Aldrich) at a dose of 0.1 mL/10 g body weight. After 0 minute, 30minutes, 1 hour and 2 hours, blood samples are collected from venousplexus of the eyeground. A blood glucose level is determined bymeasuring the serum glucose concentration in the sample using GlucoseTest B Test Wako (Wako Pure Chemical Industries). [Decrease of bloodglucose(%)=(A−B)/(A−C)×100 wherein A represents the glucoseconcentration after the loading of glucose; B represents the glucoseconcentration after the administration of a medicinal substance; and Crepresents the glucose concentration at normal times] An insulin levelis measured using Insulin Measurement Kit (EIA, Morinaga BioscienceResearch Institute) with mouse insulin as the standard.

The lipolytic activity can be examined as follows. After fasted for fourhours, a transgenic mouse is orally dosed with a test compound dissolvedin 10% hydroxypropyl-β-cyclodextrin (Aldrich) at a dose of 0.1 mL/10 gbody weight. After 0 minute, 30 minutes, 1 hour and 2 hours, bloodsamples are collected from venous plexus of the eyeground. A free fattyacid level in the serum obtained from the above sample is measured usingNEFA HA Test Wako (Wako Pure Chemical Industries).

The thermogenesis can be measured with OXYMAX System (Columbus)according to the method reported by Largis et al. (Drug DevelopmentResearch, vol. 32, pp. 69-76 (1994)). According to this device, theamount of thermogenesis can be obtained by calculating the caloriesbased on the amount of oxygen consumed and the amount of carbon dioxidegenerated. After the administration of a medicinal substance, themeasurements are carried out for 120 minutes (15 points). The average ofthe measured values obtained for the latter 90 minutes (10 points) isconverted into a value per body weight to give the amount ofthermogenesis. When a test by repetitive administrations is carried out,a medicinal substance may be administered at a dose once daily, twicedaily or the like. The duration of administration may be 1 week, 2 weeksor more. In a test by repetitive administrations, body weight, bloodglucose level and insulin level can be monitored with the passage oftime as the method of Largis et al. (Drug Development Research, vol. 32,pp. 69-76 (1994). It is also possible that after the completion of theadministration, the animal is anatomized to measure the weight of fattissue or to prepare a section followed by a microscopic examination.Further, the expression level of UCP-1 can be examined according to themethod reported by Nagase et al. (J. Clin. Invest., vol. 97, pp.2898-2904 (1996)).

The present compounds were orally administered to transgenic mice in anamount of from 3 to 10 mg/kg to measure their thermogenesis. Theadministration of the compound of Example 10, 11 or 13 resulted inincreasing the thermogenesis by 15%, 17% or 15% respectively as comparedwith the control group. These results showed that the compounds of thepresent invention posses thermogenesis increasing activities.

TEST EXAMPLE 4 Toxicity Test

Each of the present compounds synthesized in Examples 3, 9 and 10 wasorally administered to 6-week old male ddy mice (CHARLES RIVER JAPAN) at100 mg/kg, and none of eight animals were found to be dead. The othercompounds got the same results. Therefore, this test showed a lowtoxicity of the present compounds.

TABLE 3 Compound EC₅₀ (nM) Intrinsic activity* (%) Example 3 8.7 100Example 4 10 73 Example 9 16 62 Example 10 4.5 78 Example 11 4.8 80Example 12 5.3 71 Example 13 14 96 Example 17 4.4 94 *Relativeactivities (%) as compared with isoproterenol.

All the publications, patents and patent applications cited in thisspecification are incorporated herein in their entities by reference.

Industrial Utility

Compounds of the present invention are novel compounds having a highhuman β3-adrenoreceptor stimulating activity. Therefore, compounds ofthe present invention are useful as a medicine for treating andpreventing β3-adrenoreceptor associated diseases, such as diabetes,obesity, hyperlipidemia and urinary disturbances.

1. A compound of the general formula (II):

or a salt thereof, wherein W represents a hydrogen atom or anamino-protecting group; R⁵ and R⁶ may be the same or different and eachindependently represents a hydrogen atom, an alkyl group containing from1 to 6 carbon atoms, an optionally substituted phenyl group or anoptionally substituted benzyl group, provided that R⁵ and R⁶ do notrepresent a hydrogen atom at the same time; X represents NH; Yrepresents an oxygen atom, NR⁷, a sulfur atom, a methylene group or abond; and R⁷ represents a hydrogen atom, an alkyl group containing from1 to 6 carbon atoms, or an acyl group containing from 1 to 6 carbonatoms.
 2. A compound of the general formula (II):

or a salt thereof, wherein W represents a hydrogen atom or anamino-protecting group; R⁵ and R⁶ may be the same or different and eachindependently represents a hydrogen atom, an alkyl group containing from1 to 6 carbon atoms, an optionally substituted phenyl group or anoptionally substituted benzyl group, provided that R⁵ and R⁶ do notrepresent a hydrogen atom at the same time; X represents NH; Yrepresents an oxygen atom, NR⁷ or a sulfur atom; and R⁷ represents ahydrogen atom, an alkyl group containing from 1 to 6 carbon atoms, or anacyl group containing from 1 to 6 carbon atoms.
 3. The compound asclaimed in claim 2, which is a compound selected from the groupconsisting of: 2-(2,3-dimethyl-1H-indol-6-yloxy)ethylcarbamic acidbenzyl ester; 2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamine;N-benzyl-N-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethyl]amine;2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylcarbamic acid benzyl ester;2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethylamine;N-benzyl-N-[2-(3-methyl-2-phenyl-1H-indol-6-yloxy)ethyl]amine;2-(2-methyl-3-phenyl-1H-indol-6-yloxy)ethylcarbamic acid benzyl ester;2-(2-methyl-3-phenyl-1H-indol-6-yloxy)ethylamine;2-(2,3-dimethylbenzofuran-6-yloxy)ethylcarbamic acid benzyl ester;2-(2,3-dimethylbenzofuran-6-yloxy)ethylamine;N-benzyl-N-[2-(2,3-dimethylbenzofuran-6-yloxy)ethyl]amine;2-(2,3-dimethylbenzothiophen-6-yloxy)ethylcarbamic acid benzyl ester;2-(2,3-dimethylbenzothiophen-6-yloxy)ethylamine; andN-benzyl-N-[2-(2,3-dimethylbenzothiophen-6-yloxy)ethyl]amine; or a saltthereof.